1,4-sulfur-bridged polycyclic compounds containing dihydrobenzofuran structure, its preparation method and application thereof

Abstract

The present invention discloses a 1,4-sulfur-bridged polycyclic compound containing dihydrobenzofuran structure which has a structural formula (I). A preparation method is also disclosed which includes the steps of: dissolving 2-nitrobenzofuran (II) and 5H-thiazolone (III) in an organic solvent; then adding molecular sieve and chiral catalyst, stirring and allowing reaction at room temperature under argon protection until the reaction is completed; and carrying out separation and purification to obtain a 1,4-sulfur-bridged polycyclic compound (I) containing dihydrobenzofuran structure. The polycyclic compounds of the present invention have a substructure of dihydrobenzofuran and 1,4-thiopiperidinone. The application of the compound for the preparation of antitumor drugs is also disclosed, which has a good potential value in antitumor drug research. The preparation method has the advantages of novelty, simplicity, simple operation, mild reaction conditions, high yield and high stereoselectivity, and etc.

Claims

1. A 1,4-sulfur-bridged polycyclic compounds containing a dihydrobenzofuran structure, characterized in that, having a structural formula (I) as follows: ##STR00027## in the above structure formula, Ar is one of substituted aromatic rings and heteroaromatic rings, wherein R.sup.1 group is a single substituent or a multi-substituted group, wherein the substituent is selected from a group consisting of hydrogen, alkyl, alkoxy, nitro and halogen, wherein R.sup.2 group is selected from a group consisting of methyl, ethyl and benzyl.

2. A preparation method of 1,4-sulfur-bridged polycyclic compounds containing a dihydrobenzofuran structure according to claim 1, characterized in that: dissolving 2-nitrobenzofuran (II) and 5H-thiazolone (III) in an organic solvent; then adding molecular sieve and chiral catalyst; stirring and allowing reaction at room temperature under argon protection; and carrying out separation and purification after the reaction is completed to obtain a 1,4-sulfur-bridged polycyclic compound (I) containing dihydrobenzofuran structure, wherein the 2-nitrobenzofuran (II) has a structure as follows: ##STR00028## the 5H-thiazolone (III) has a structure as follows: ##STR00029##

3. The preparation method according to claim 2, characterized in that: the organic solvent is selected from a group consisting of one or a mixture of: toluene, mesitylene, dichloromethane, chloroform, tetrahydrofuran, ether, acetonitrile, ethanol, methanol, 1,4-dioxane, and chlorobenzene.

4. The preparation method according to claim 3, characterized in that: the organic solvent is dichloromethane.

5. The preparation method according to claim 2, characterized in that: the chiral catalyst is a chiral tertiary amine-thiourea bifunctional catalyst or a chiral tertiary amine-squaramide bifunctional catalyst.

6. The preparation method according to claim 2, characterized in that: the molar ratio of the reaction substrate is n.sub.II:n.sub.III=2:11:2.

7. The preparation method according to claim 6, characterized in that: the molar ratio of the reaction substrate is n.sub.II:n.sub.III=1:1.3.

8. The 1,4-sulfur-bridged polycyclic compounds containing a dihydrobenzofuran structure according to claim 1, wherein the 1,4-sulfur-bridged polycyclic compounds containing a dihydrobenzofuran structure is prepared into an antitumor medicament having inhibitory effect on human leukemia cell K562 and human lung cancer cell A549.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is a diagram illustrating an asymmetric reaction structure of a nitroaromatic heterocycle according to a preferred embodiment of the present invention.

(2) FIG. 2 illustrates a hydrogen spectrogram of the I-ea obtained in Example 5.

(3) FIG. 3 illustrates a carbon spectrogram of the I-ea prepared in Example 5.

(4) FIG. 4 illustrates a single crystal diagram of the I-ea prepared in Example 5.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

(5) The following description in conjunction with the accompanying drawings is further disclosed.

(6) The raw materials, solvents, catalysts, molecular sieves, etc. disclosed in the present invention are all commercially available.

Example 1: Synthetic Compound I-aa

(7) ##STR00006##

(8) Add 0.2 mmol of 2-nitrobenzofuran II-a, 0.26 mmol of 5H-thiazolone III-a, 100 mg of 5A molecular sieve and chiral catalyst A/B/C/D into a dry test tube. Then, add 2.0 mL of solvent, and the reaction is carried out at room temperature under argon protection. After the reaction is completed, the crude product is separated and purified by column chromatography to obtain compound I-aa, wherein different reaction conditions are as shown in Table 2, and the concrete reaction process is as follows:

(9) ##STR00007##

(10) TABLE-US-00002 TABLE 2 Different reaction conditions Time Molecular Yield ee SN Catalyst x Solvent (h) Sieve Ar (%) dr (%) 1 A 20 CHCl.sub.3 20 No No 40 >20:1 73 2 B 20 CHCl.sub.3 20 No No 41 >20:1 61 3 C 20 CHCl.sub.3 10 No No 39 >20:1 64 4 D 20 CHCl.sub.3 24 No No 33 >20:1 85 5 D 20 CH.sub.2Cl.sub.2 24 No No 31 >20:1 93 6 D 20 (CH.sub.2Cl).sub.2 24 No No 30 >20:1 93 7 D 20 CH.sub.2Cl.sub.2 24 Yes No 60 >20:1 91 8 D 20 CH.sub.2Cl.sub.2 24 Yes Yes 85 >20:1 94 9 D 10 CH.sub.2Cl.sub.2 48 Yes Yes 83 >20:1 94 10 D 5 CH.sub.2Cl.sub.2 72 Yes Yes 78 >20:1 93

(11) In Table 1, X represents the molar percentage of the catalyst being used.

(12) As shown in Table 1, it is preferred that 20 mol % of catalyst D, dichloromethane as solvent, adding molecular sieve additive are preferred for reaction under argon protection.

(13) The obtained compound I-aa is a white solid with a purity of >99% detected by HPLC; >20:1 dr, 94% ee; [].sub.D.sup.20=182.6 (c 1.0, CH2Cl2); m.p. 163.1-164.0 C.

(14) Wherein, the ee value is determined by HPLC method: Chiralpak IC column; mobile phase 90/10 hexane/EtOH; flow rate: 1.0 mL/min; detection wavelength =220 nm; retention time t.sub.major=15.79 min, t.sub.minor=10.01 min.

(15) Structure identification: .sup.1H NMR (300 MHz, DMSO-d.sub.6) 10.20 (s, 1H), 7.62-7.53 (m, 2H), 7.53-7.44 (m, 4H), 7.44-7.34 (m, 1H), 7.23-7.10 (m, 2H), 4.81 (s, 1H), 1.60 (s, 3H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) 206.1, 176.2, 160.0, 130.4, 129.9, 129.2, 128.7, 127.1, 126.1, 125.8, 123.2, 123.0, 110.3, 81.6, 62.5, 59.5, 11.8. HRMS (ESI-TOF) Calcd. for C.sub.18H.sub.15N.sub.2O.sub.4S [M+H].sup.+: 355.0747; found: 355.0747.

(16) The measurement results are shown in FIG. 4, indicating that the absolute configuration of compound I-ea is (C2R, C15S, C16S, C17R). By analogy, the compounds of the present invention are all in this configuration.

Example 2: Synthetic Compound I-ba

(17) ##STR00008##

(18) Add 0.2 mmol of 2-nitrobenzofuran II-b, 0.26 mmol of 5H-thiazolone III-a, 5A 100 mg of molecular sieve and 0.02 mmol of chiral catalyst D into a dry test tube. Then, add 2.0 mL of dichloromethane, wherein the reaction is carried out at room temperature under the argon protection. After the reaction is completed, the crude product is separated and purified by column chromatography to obtain compound I-ba.

(19) Pale yellow solid; 87% yield; >20:1 dr, 94% ee; m.p. 178.5-179.5 C., [].sub.D.sup.25=425.5 (c 1.0, CH.sub.2Cl.sub.2).

(20) Wherein, the ee value is determined by HPLC method: Chiralpak IC column; mobile phase 95/5 hexane/EtOH; flow rate: 1.0 mL/min; detection wavelength =220 nm; t.sub.major=21.78 min, t.sub.minor=12.01 min.

(21) Structural identification: .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.23 (s, 1H), 7.59-7.53 (m, 2H), 7.51-7.45 (m, 3H), 7.37 (dd, J=8.1, 2.4 Hz, 1H), 7.26-7.18 (m, 2H), 4.83 (s, 1H), 1.61 (s, 3H). .sup.13C NMR (101 MHz, DMSO-d.sub.6) 176.5, 159.6, 157.2, 156.7, 130.5, 129.1, 128.1 (d, J=266.6 Hz, 1C), 127.6, 125.3 (d, J=9.1 Hz, 1C), 117.3 (d, J=25.2 Hz, 1C), 113.7 (d, J=26.3 Hz, 1C), 111.6 (d, J=9.0 Hz, 1C), 82.1, 62.8, 60.0, 12.3. HRMS (ESI-TOF) Calcd. for C.sub.18H.sub.13FN.sub.2NaO4S [M+Na].sup.+: 395.0472; found: 395.0466.

Example 3: Synthetic Compound I-ca

(22) ##STR00009##

(23) Add 0.2 mmol of 2-nitrobenzofuran II-c, 0.26 mmol of 5H-thiazolone III-a, 100 mg of 5A molecular sieve and 0.02 mmol of chiral catalyst D into a dry test tube. Then, add 2.0 mL of dichloromethane, wherein the reaction is carried out at room temperature under the argon protection. After the reaction is completed, the crude product is separated and purified by column chromatography to obtain compound I-ca.

(24) Pale yellow solid; 95% yield; >20:1 dr, 90% ee; m.p. 138.2-139.1 C., [].sub.D.sup.25=538.6 (c 1.0, CH.sub.2Cl.sub.2).

(25) Wherein, the ee value is determined by HPLC method: Chiralpak IC column; mobile phase 90/10 hexane/EtOH; flow rate: 1.0 mL/min; detection wavelength =220 nm; t.sub.major=23.51 min, t.sub.minor=14.52 min.

(26) Structure identification: .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.28 (s, 1H), 7.58 (dd, J=6.8, 3.0 Hz, 2H), 7.55-7.47 (m, 3H), 7.43-7.29 (m, 2H), 7.21-7.11 (m, 1H), 4.94 (s, 1H), 1.61 (s, 3H). .sup.13C NMR (101 MHZ, DMSO-d.sub.6) 176.4, 146.7 (d, J=11.1 Hz, 1C) 146.5 (d, J=247.4 Hz, 1C), 130.6, 129.2, 127.5, 127.4, 126.6, 124.5 (d, J=5.0 Hz, 1C), 122.4, 122.3, 117.9 (d, J=16.2 Hz, 1C), 82.2, 62.9, 60.4, 55.4, 12.3. HRMS (ESI-TOF) Calcd. for C.sub.18H.sub.13FN.sub.2NaO.sub.4S [M+Na].sup.+: 395.0472; found: 395.0465.

Example 4: Synthetic Compound I-da

(27) ##STR00010##

(28) Add 0.2 mmol of 2-nitrobenzofuran II-d, 0.26 mmol of 5H-thiazolone III-a, 100 mg of 5A molecular sieve and 0.02 mmol of chiral catalyst D into a dry test tube. Then, add 2.0 mL of dichloromethane, wherein the reaction is carried out at room temperature under the argon protection. After the reaction is completed, the crude product is separated and purified by column chromatography to obtain compound I-da.

(29) Pale yellow solid; 90% yield; >20:1 dr, 84% ee; m.p. 144.3-145.2 C., [].sub.D.sup.25=345.6 (c 1.0, CH.sub.2C.sub.l2).

(30) Wherein, the ee value is determined by HPLC method: Chiralpak IC column; mobile phase 95/5 hexane/.sup.iPrOH; flow rate: 1.0 mL/min; detection wavelength =220 nm; t.sub.major=9.46 min, t.sub.minor=7.60 min.

(31) Structure identification: .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.34 (s, 1H), 7.60-7.54 (m, 2H), 7.54-7.48 (m, 3H), 7.47-7.41 (m, 1H), 7.22 (dd, J=11.6, 8.1 Hz, 2H), 4.86 (s, 1H), 1.66 (s, 3H). .sub.13C NMR (101 MHz, DMSO-d.sub.6) 176.2, 161.4, 132.7, 130.8, 130.6, 129.2, 129.1, 127.6, 125.7, 124.5, 122.4, 110.1, 81.9, 64.8, 60.1, 14.8. HRMS (ESI-TOF) Calcd. for C.sub.18H.sub.13ClN.sub.2NaO.sub.4S [M+Na].sup.+: 411.0177; found: 411.0159.

Example 5: Synthetic Compound I-ea

(32) ##STR00011##

(33) Add 0.2 mmol of 2-nitrobenzofuran II-e, 0.26 mmol of 5H-thiazolone III-a, 100 mg of 5A molecular sieve and 0.02 mmol of chiral catalyst D into a dry test tube. Then, add 2.0 mL of dichloromethane, wherein the reaction is carried out at room temperature under the argon protection. After the reaction is completed, the crude product is separated and purified by column chromatography to obtain compound I-ea.

(34) White solid; 90% yield; >20:1 dr, 93% ee; m.p. 155.3-156.2 C., [].sub.D.sup.25=419.1 (c 1.0, CH.sub.2Cl.sub.2).

(35) Wherein, the ee value is determined by HPLC method: Chiralpak IC column; mobile phase 90/10 hexane/EtOH; flow rate: 1.0 mL/min; detection wavelength =220 nm; t.sub.major=11.11 min, t.sub.minor=7.89 min.

(36) Structure identification: .sup.1H NMR (400 MHZ, DMSO-d.sub.6) (shown in FIG. 2) 10.25 (s, 1H), 7.61-7.54 (m, 3H), 7.53-7.47 (m, 3H), 7.45 (dd, J=8.6, 2.3 Hz, 1H), 7.23 (d, J=8.6 Hz, 1H), 4.85 (s, 1H), 1.62 (s, 3H). .sup.13C NMR (101 MHz, DMSO-d.sub.6) (shown in FIG. 3) 176.4, 159.3, 130.7, 130.5, 129.3, 129.2, 127.5, 127.3, 126.5, 126.4, 126.0, 112.3, 82.1, 62.8, 59.8, 12.3. HRMS (ESI-TOF) Calcd. for C.sub.18H.sub.13ClN.sub.2NaO.sub.4S [M+Na].sup.+: 411.0177; found: 411.0161.

Single Crystal Diffraction Experiment

(37) Single crystal cultivation: The main component compound I-ea (40 mg) obtained in Example 5 is dissolved in 20 mL of a mixture of dichloromethane and ethanol (V.sub.dichloromethane:V.sub.dichloromethane=1:10). After resting at room temperature for 7 days, a single crystal is precipitated, and the single crystal is collected for single crystal diffraction test. The test parameters are shown in Table 3.

(38) TABLE-US-00003 TABLE 3 Single crystal test parameters Identification code I-ea Empirical formula C.sub.20H.sub.19ClN.sub.2O.sub.5S.sub.2 Formula weight 466.94 Temperature/K 293(2) Crystal system monoclinic Space group C2 a/ 26.7417(6) b/ 6.38250(16) c/ 12.8324(3) / 90 / 103.440(2) / 90 Volume/.sup.3 2130.24(9) Z 4 .sub.calc g/cm.sup.3 1.456 /mm.sup.1 3.728 F(000) 968.0 Crystal size/mm.sup.3 0.17 0.12 0.09 Radiation CuK ( = 1.54184) 2range for data collection/ 6.796 to 134.108 Index ranges 28 h 31, 7 k 7, 15 l 15 Reflections collected 7977 Independent reflections 3813 [R.sub.int = 0.0320, R.sub.sigma = 0.0422] Data/restraints/parameters 3813/1/278 Goodness-of-fit on F.sup.2 1.027 Final R indexes [I >= 2 (I)] R1 = 0.0425, wR2 = 0.1083 Final R indexes [all data] R1 = 0.0462, wR2 = 0.1133 Largest diff. peak/hole/e .sup.3 0.23/0.46 Flack parameter 0.001(14)

(39) The measurement results are shown in FIG. 4, indicating that the absolute configuration of compound I-ea is (C2S, C3R, C4R, C5S). By analogy, the compounds of the present invention are all in this configuration.

Example 6: Synthetic Compound I-fa

(40) ##STR00012##

(41) Add 0.2 mmol of 2-nitrobenzofuran II-f, 0.26 mmol of 5H-thiazolone III-a, 100 mg of 5A molecular sieve and 0.02 mmol of chiral catalyst D into a dry test tube. Then, add 2.0 mL of dichloromethane, wherein the reaction is carried out at room temperature under the argon protection. After the reaction is completed, the crude product is separated and purified by column chromatography to obtain compound I-fa.

(42) White solid; 86% yield; >20:1 dr, 92% ee; m.p. 149.3-150.3 C., [].sub.D.sup.25=444.4 (c 1.0, CH.sub.2Cl.sub.2).

(43) Wherein, the ee value is determined by HPLC method: Chiralpak IC column; mobile phase 90/10 hexane/EtOH; flow rate: 1.0 mL/min; detection wavelength =220 nm; t.sub.major=10.66 min, t.sub.minor=8.61 min.

(44) Structure identification: .sup.1H NMR (400 MHZ, DMSO-d6) 10.25 (s, 1H), 7.68 (d, J=2.1 Hz, 1H), 7.61-7.54 (m, 3H), 7.53-7.45 (m, 3H), 7.18 (d, J=8.6 Hz, 1H), 4.86 (s, 1H), 1.61 (s, 3H). .sup.13C NMR (101 MHz, DMSO-d.sub.6) 176.4, 159.8, 133.5, 130.5, 129.3, 129.2, 129.1, 127.6, 126.5, 126.4, 114.9, 112.8, 82.1, 62.8, 59.8, 12.3. HRMS (ESI-TOF) Calcd. for C.sub.18H.sub.13.sup.79BrN.sub.2NaO.sub.4S [M+Na].sup.+: 454.9672; found: 454.9653; For C.sub.18H.sub.13.sup.81BrN.sub.2NaO.sub.4S [M+Na].sup.+: 456.9651; found: 454.9630.

Example 7: Synthetic Compound I-ga

(45) ##STR00013##

(46) Add 0.2 mmol of 2-nitrobenzofuran II-g, 0.26 mmol of 5H-thiazolone III-a, 100 mg of 5A molecular sieve and 0.02 mmol of chiral catalyst D into a dry test tube. Then, add 2.0 mL of dichloromethane, wherein the reaction is carried out at room temperature under the argon protection. After the reaction is completed, the crude product is separated and purified by column chromatography to obtain compound I-ga.

(47) White solid; 86% yield; >20:1 dr, 92% ee; m.p. 161.8-162.8 C., [60 ].sub.D.sup.25=597.1 (c 1.0, CH.sub.2Cl.sub.2).

(48) Wherein, the ee value is determined by HPLC method: Chiralpak IC column; mobile phase 90/10 hexane/EtOH; flow rate: 1.0 mL/min; detection wavelength =220 nm; t.sub.major=28.17 min, t.sub.minor=15.67 min.

(49) Structural identification: .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.24 (s, 1H), 7.60-7.54 (m, 2H), 7.53-7.47 (m, 4H), 7.43 (d, J=8.1 Hz, 1H), 7.35 (dd, J=8.0, 1.8 Hz, 1H), 4.81 (s, 1H), 1.59 (s, 3H). .sup.13C NMR (101 MHz, DMSO-d.sub.6) 176.4, 161.2, 130.5, 129.3, 129.1, 128.0, 127.6, 126.5, 126.4, 123.5, 123.0, 114.1, 82.1, 62.8, 59.5, 12.2. HRMS (ESI-TOF) Calcd. for C.sub.18H.sub.13.sup.79BrN.sub.2NaO.sub.4S [M+Na].sup.+: 454.9672; found: 454.9662; For C.sub.18H.sub.13.sup.81BrN.sub.2NaO.sub.4S [M+Na].sup.+: 456.9651; found: 454.9642.

Example 8: Synthetic Compound I-ha

(50) ##STR00014##

(51) Add 0.2 mmol of 2-nitrobenzofuran II-h, 0.26 mmol of 5H-thiazolone III-a, 100 mg of 5A molecular sieve and 0.02 mmol of chiral catalyst D into a dry test tube. Then, add 2.0 mL of dichloromethane, wherein the reaction is carried out at room temperature under the argon protection. After the reaction is completed, the crude product is separated and purified by column chromatography to obtain compound I-ha.

(52) Yellow solid; 80% yield; >20:1 dr, 88% ee; m.p. 222.8-223.5 C., [].sub.D.sup.25=47.9 (c 0.5, CH.sub.2Cl.sub.2).

(53) Accordingly, the ee value is determined by HPLC method: Chiralpak IC column; mobile phase 70/30 hexane/EtOH; flow rate: 1.0 mL/min; detection wavelength =220 nm; t.sub.major=9.73 min, t.sub.minor=10.65 min.

(54) Structural identification: .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.33 (s, 1H), 8.43-8.27 (m, 2H), 7.58-7.54 (m, 2H), 7.54-7.48 (m, 3H), 7.45 (d, J=8.9 Hz, 1H), 5.75 (s, 1H), 1.66 (s, 3H). .sup.13C NMR (101 MHZ, DMSO-d.sub.6) 176.2, 164.8, 143.8, 130.7, 129.7, 129.2, 129.0, 128.4, 127.7, 127.5, 126.7, 125.9, 122.6, 111.4, 82.3, 62.9, 59.2, 12.1. HRMS (ESI-TOF) Calcd. for C.sub.18H.sub.13N.sub.3NaO.sub.6S [M+Na].sup.+: 422.0417; found: 422.0403.

Example 9: Synthetic Compound I-ia

(55) ##STR00015##

(56) Add 0.2 mmol of 2-nitrobenzofuran II-i, 0.26 mmol of 5H-thiazolone III-a, 100 mg of 5A molecular sieve and 0.02 mmol of chiral catalyst D into a dry test tube. Then, add 2.0 mL of dichloromethane, wherein the reaction is carried out at room temperature under the argon protection. After the reaction is completed, the crude product is separated and purified by column chromatography to obtain compound I-ia.

(57) White solid; 78% yield; >20:1 dr, 89% ee; m.p. 140.2-140.9 C., [].sub.D.sup.25=284.3 (c 1.0, CH.sub.2Cl.sub.2).

(58) Wherein, the ee value is determined by HPLC method: Chiralpak IC column; mobile phase 90/10 hexane/EtOH; flow rate: 1.0 mL/min; detection wavelength =220 nm; t.sub.major=10.12 min, t.sub.minor=7.33 min.

(59) Structure identification: .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.18 (s, 1H), 7.58 (dd, J=6.8, 3.0 Hz, 2H), 7.53-7.45 (m, 3H), 7.35 (d, J=7.7 Hz, 1H), 7.01 (s, 1H), 6.96 (d, J=7.7 Hz, 1H), 4.74 (s, 1H), 2.34 (s, 3H), 1.58 (s, 3H). .sup.13C NMR (101 MHz, DMSO-d.sub.6) 176.7, 160.8, 141.0, 130.4, 129.7, 129.1, 127.5, 126.5, 126.1, 124.1, 120.7, 111.2, 82.0, 63.0, 59.8, 21.6, 12.3. HRMS (ESI-TOF) Calcd. for C.sub.19H.sub.16N.sub.2NaO.sub.4S [M+Na].sup.+: 391.0723; found: 391.0710.

Example 10: Synthetic Compound I-ja

(60) ##STR00016##

(61) Add 0.2 mmol of 2-nitrobenzofuran II-j, 0.26 mmol of 5H-thiazolone III-a, 100 mg of 5A molecular sieve and 0.02 mmol of chiral catalyst D into a dry test tube. Then, add 2.0 mL of dichloromethane, wherein the reaction is carried out at room temperature under the argon protection. After the reaction is completed, the crude product is separated and purified by column chromatography to obtain compound I-ja.

(62) White solid; 78% yield; >20:1 dr, 88% ee; m.p. 188.7-189.5 C., [].sup.25=219.5 (c 1.0, CH.sub.2Cl.sub.2).

(63) Accordingly, the ee value is determined by HPLC method: Chiralpak IC column; mobile phase 90/10 hexane/EtOH; flow rate: 1.0 mL/min; detection wavelength =220 nm; t.sub.major=12.69 min, t.sub.minor=9.04 min.

(64) Structure identification: .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.16 (s, 1H), 7.57 (dd, J=6.8, 3.0 Hz, 2H), 7.52-7.46 (m, 3H), 7.35 (d, J=8.4 Hz, 1H), 6.84 (d, J=2.3 Hz, 1H), 6.70 (dd, J=8.4, 2.3 Hz, 1H), 4.70 (s, 1H), 3.78 (s, 3H), 1.57 (s, 3H). .sup.13C NMR (101 MHz, DMSO-d.sub.6) 176.7, 162.0, 161.8, 130.4, 129.6, 129.1, 127.5, 127.0, 126.7, 115.2, 109.7, 97.0, 81.9, 63.1, 59.6, 56.2, 12.2. HRMS (ESI-TOF) Calcd. for C.sub.19H.sub.16N.sub.2NaO.sub.5 S [M+Na].sup.+: 407.0672; found: 407.0656.

Example 11: Synthetic Compound I-ka

(65) ##STR00017##

(66) Add 0.2 mmol of 2-nitrobenzofuran II-k, 0.26 mmol of 5H-thiazolone III-a, 100 mg of 5A molecular sieve and 0.02 mmol of chiral catalyst D into a dry test tube. Then, add 2.0 mL of dichloride Methane, wherein the reaction is carried out at room temperature under argon protection. After the reaction is complete, the crude product is separated and purified by column chromatography to obtain compound I-ka.

(67) White solid; 70% yield; >20:1 dr, 89% ee; m.p. 177.4-178.3 C., [].sub.D.sup.25=214.1 (c 1.0, CH.sub.2Cl.sub.2).

(68) Wherein, the ee value is determined by HPLC method: Chiralpak IC column; mobile phase 95/5 hexane/EtOH; flow rate: 1.0 mL/min; detection wavelength =220 nm; t.sub.major=11.02 min, t.sub.minor=8.88 min.

(69) Structure identification: .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.19 (s, 1H), 7.62-7.55 (m, 2H), 7.49 (dd, J=4.3, 2.3 Hz, 4H), 7.41 (dd, J=8.5, 2.1 Hz, 1H), 7.09 (d, J=8.6 Hz, 1H), 4.76 (s, 1H), 1.61 (s, 3H), 1.30 (s, 9H). .sup.13C NMR (101 MHz, DMSO-d.sub.6) 176.7, 158.5, 146.1, 130.4, 129.9, 129.7, 129.1, 127.6, 127.5, 126.6, 123.4, 123.3, 109.9, 81.9, 62.9, 60.1, 34.8, 31.8, 12.4. HRMS (ESI-TOF) Calcd. for C.sub.22H.sub.22N.sub.2NaO.sub.5S [M+Na].sup.+: 433.1192; found: 433.1181.

Example 12: Synthetic Compound I-la

(70) ##STR00018##

(71) Add 0.2 mmol of 2-nitrobenzofuran II-l, 0.26 mmol of 5H-thiazolone III-a, 100 mg of 5A molecular sieve and 0.02 mmol of chiral catalyst D into a dry test tube. Then, add 2.0 mL of dichloromethane, wherein the reaction is carried out at room temperature under the argon protection. After the reaction is complete, the crude product is separated and purified by column chromatography to obtain compound I-la.

(72) White solid; 94% yield; >20:1 dr, 91% ee; m.p. 156.9-157.7 C., [].sub.D.sup.25=285.5 (c 1.0, CH.sub.2Cl.sub.2).

(73) Accordingly, the ee value is determined by HPLC method: Chiralpak IC column; mobile phase 95/5 hexane/.sup.iPrOH; flow rate: 1.0 mL/min; detection wavelength =220 nm; t.sub.major=32.45 min, t.sub.minor=39.30 min.

(74) Structure identification: .sup.1H NMR (300 MHZ, DMSO-d.sub.6) 10.22 (s, 1H), 7.58-7.45 (m, 5H), 7.33-7.22 (m, 2H), 4.85 (s, 1H), 3.87 (s, 3H), 1.59 (s, 3H). .sup.13C NMR (101 MHz, DMSO-d.sub.6) 176.6, 148.7, 144.4, 130.4, 130.0, 129.6, 129.1, 129.0, 127.6, 126.5, 124.8, 124.2, 118.0, 114.3, 82.0, 62.9, 60.5, 56.4, 12.4. HRMS (ESI-TOF) Calcd. for C.sub.19H.sub.15.sup.79BrN.sub.2NaO.sub.5S [M+Na].sup.+: 484.9777; found: 484.9764; For C.sub.19H.sub.15.sup.81BrN.sub.2NaO.sub.5S [M+Na].sup.+: 486.9757; found: 486.9739.

Example 13: Synthetic Compound I-ab

(75) ##STR00019##

(76) Add 0.2 mmol of 2-nitrobenzofuran II-a, 0.26 mmol of 5H-thiazolone III-b, 100 mg of 5A molecular sieve and 0.02 mmol of chiral catalyst D into a dry test tube. Then, add 2.0 mL of dichloromethane, wherein the reaction is carried out at room temperature under argon protection. After the reaction is completed, the crude product is separated and purified by column chromatography to obtain compound I-ab.

(77) White solid; 60% yield; >20:1 dr, 89% ee; m.p. 160.7-161.5 C., [].sup.25=171.5 (c 0.5, CH.sub.2Cl.sub.2).

(78) Wherein, the ee value is determined by HPLC method: Chiralpak IC column; mobile phase 90/10 hexane/EtOH; flow rate: 1.0 mL/min; detection wavelength =220 nm; t.sub.major=23.50 min, t.sub.minor=14.23 min.

(79) Structure identification: .sup.1H NMR (300 MHz, DMSO-d.sub.6) 10.05 (s, 1H), 7.56(dd, J=14.6, 7.4 Hz, 2H), 7.47 (d, J=7.7 Hz, 1H), 7.41-7.31 (m, 3H), 7.17-7.10 (m, 2H), 4.80 (s, 1H), 1.59 (s, 3H). .sup.13C NMR (151 MHz, DMSO-d.sub.6) 176.2, 160.6 (d, J=250.7 Hz, 1C), 160.5, 133.2 (d, J=9.1 Hz, 1C), 130.8, 130.4 (d, J=3.0 Hz, 1C), 126.5, 125.7, 125.2 (d, J=4.5 Hz, 1C), 123.7, 123.4, 117.2 (d, J=22.6 Hz, 1C), 116.5 (d, J=10.6 Hz. 1C), 110.7, 79.8 (d, J=3.0 Hz, 1C), 62.4, 59.9, 12.2. HRMS (ESI-TOF) Calcd. for C.sub.18H.sub.14FN.sub.2O.sub.4S [M+H].sup.+: 373.0653; found: 373.0652.

Example 14: Synthetic Compound I-ac

(80) ##STR00020##

(81) Add 0.2 mmol of 2-nitrobenzofuran II-a, 0.26 mmol of 5H-thiazolone III-c, 100 mg of 5A molecular sieve and 0.02 mmol of chiral catalyst D into a dry test tube. Then, add 2.0 mL of dichloromethane, wherein the reaction is carried out at room temperature under argon protection. After the reaction is completed, the crude product is separated and purified by column chromatography to obtain compound I-ac.

(82) White solid; 72% yield; >20:1 dr, 93% ee ; m.p. 173.4-174.1 C., [].sub.D.sup.25=64.2 (c 0.5, CH.sub.2Cl.sub.2).

(83) Wherein, the ee value is determined by HPLC method: Chiralpak IC column; mobile phase 80/20 hexane/EtOH; flow rate: 1.0 mL/min; detection wavelength =220 nm; t.sub.major=11.64 min, t.sub.minor=16.50 min.

(84) Structure identification: .sup.1H NMR (300 MHz, DMSO-d.sub.6) 10.16 (s, 1H), 7.53-7.44 (m, 3H), 7.43-7.35 (m, 1H), 7.20-7.11 (m, 2H), 7.06-7.01 (m, 2H), 4.79 (s, 1H), 1.58 (s, 3H). .sup.13C NMR (151 MHz, DMSO-d.sub.6) 176.6, 163.3 (d, J=249.2 Hz, 1C), 160.4, 130.8, 130.0 (d, J=9.1 Hz, 2C), 126.6, 126.2, 126.0 (d, J=3.0 Hz, 1C), 123.6, 123.5, 116.2 (d, J=22.6 Hz, 2C), 110.7, 81.3, 63.1, 59.8, 12.3. HRMS (ESI-TOF) Calcd. for C.sub.18H.sub.14FN.sub.2O.sub.4S [M+H].sup.+: 373.0653; found: 373.0662.

Example 15: Synthetic Compound I-ad

(85) ##STR00021##

(86) Add 0.2 mmol of 2-nitrobenzofuran II-a, 0.26 mmol of 5H-thiazolone III-d, 100 mg of 5A molecular sieve and 0.02 mmol of chiral catalyst D into a dry test tube. Then, add 2.0 mL of dichloromethane, wherein the reaction is carried out at room temperature under the argon protection. After the reaction is completed, the crude product is separated and purified by column chromatography to obtain compound I-ad.

(87) White solid; 78% yield; >20:1 dr, 98% ee; m.p. 186.0-186.7 C., [].sub.D.sup.25=389.3 (c 0.5, CH.sub.2Cl.sub.2).

(88) Wherein, the ee value is determined by HPLC method: Chiralpak IC column; mobile phase 90/10 hexane/EtOH; flow rate: 1.0 mL/min; detection wavelength =220 nm; t.sub.major=13.93 min, t.sub.minor=8.09 min.

(89) Structure identification: .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.25 (s, 1H), 7.66-7.56 (m, 4H), 7.53-7.46 (m, 1H), 7.45-7.37 (m, 1H), 7.22-7.12 (m, 2H), 4.85 (s, 1H), 1.60 (s, 3H). .sup.13C NMR (101 MHZ, DMSO-d.sub.6) 176.6, 160.5, 135.3, 130.9, 129.5, 129.2, 128.7, 126.6, 126.2, 123.6, 123.5, 110.8, 81.2, 63.1, 59.8, 12.3. HRMS (ESI-TOF) Calcd. for C.sub.18H.sub.14ClN.sub.2O.sub.4S [M+H].sup.+: 389.0357; found: 389.0364.

Example 16: Synthetic Compound I-ae

(90) ##STR00022##

(91) Add 0.2 mmol of 2-nitrobenzofuran II-a, 0.26 mmol of 5H-thiazolone III-e, 100 mg of 5A molecular sieve and 0.02 mmol of chiral catalyst D into a dry test tube. Then, add 2.0 mL of dichloromethane, wherein the reaction is carried out at room temperature under the argon protection. After the reaction is completed, the crude product is separated and purified by column chromatography to obtain compound I-ae.

(92) White solid; 72% yield; >20:1 dr, 96% ee; m.p. 175.7-176.6 C., [].sub.D.sup.25=37.8 (c 0.5, CH.sub.2Cl.sub.2).

(93) Wherein, the ee value is determined by HPLC method: Chiralpak IC column; mobile phase 90/10 hexane/EtOH; flow rate: 1.0 mL/min; detection wavelength =220 nm; t.sub.major=11.44 min, t.sub.minor=9.76 min.

(94) Structure identification: .sup.1H NMR (300 MHZ, DMSO-d.sub.6) 10.25 (s, 1H), 7.79-7.67 (m, 2H), 7.58-7.45 (m, 3H), 7.44-7.35 (m, 1H), 7.22-7.08 (m, 2H), 4.84 (s, 1H), 1.59 (s, 3H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) 176.4, 160.2, 131.9, 130.6, 129.4, 128.8, 126.3, 125.9, 123.8, 123.3, 123.2, 110.5, 81.0, 62.9, 59.5, 12.0. HRMS (ESI-TOF) Calcd. for C.sub.18H.sub.14.sup.79BrN.sub.2O.sub.4S [M+H].sup.+: 432.9858; found: 432.9852; For C.sub.18H.sub.14.sup.81BrN.sub.2O.sub.4S [M+H].sup.+: 434.9833; found: 434.9843.

Example 17: Synthetic Compound I-af

(95) ##STR00023##

(96) Add 0.2 mmol of 2-nitrobenzofuran II-a, 0.26 mmol of 5H-thiazolone III-f, 100 mg of 5A molecular sieve and 0.02 mmol of chiral catalyst D into a dry test tube. Then, add 2.0 mL of dichloromethane, wherein the reaction is carried out at room temperature under the argon protection. After the reaction is completed, the crude product is separated and purified by column chromatography to obtain compound I-af.

(97) White solid; 75% yield; >20:1 dr, 90% ee; m.p. 224.0-224.8 C., [].sub.D.sup.25=112.3 (c 0.5, CH.sub.2Cl.sub.2).

(98) Wherein, the ee value is determined by HPLC method: Chiralpak IC column; mobile phase 80/20 hexane/EtOH; flow rate: 1.0 mL/min; detection wavelength =220 nm; t.sub.major=32.08 min, t.sub.minor=17.18 min.

(99) Structure identification: .sup.1H NMR (300 MHZ, DMSO-d.sub.6) 10.08 (s, 1H), 7.99-7.82 (m, 1H), 7.62-7.54 (m, 1H), 7.47 (d, J=7.1 Hz, 1H), 7.42-7.35 (m, 1H), 7.34-7.26 (m, 1H), 7.19-7.10 (m, 2H), 4.82 (s, 1H), 1.60 (s, 3H). .sup.13C NMR (101 MHz, DMSO-d.sub.6) 176.1, 160.5, 156.7 (d, J=253.5 Hz, 1C), 136.3, 130.9, 129.9, 126.6, 126.4 (d, J=4.0 Hz, 1C), 125.7, 123.6 (d, J=8.1 Hz, 1C), 118.5 (d, J=13.1 Hz, 1C), 110.8, 110.3 (d, J=22.2 Hz, 1C), 79.4, 79.4, 62.7, 59.9, 12.2. HRMS (ESI-TOF) Calcd. for C.sub.18H.sub.13.sup.79BrFN.sub.2O.sub.4S [M+H].sup.+: 450.9783; found: 450.9758; For C.sub.18H.sub.13.sup.81BrFN.sub.2O.sub.4S [M+H].sup.+: 452.9739; found: 452.9712.

Example 18: Synthetic Compound I-ag

(100) ##STR00024##

(101) Add 0.2 mmol of 2-nitrobenzofuran II-a, 0.26 mmol of 5H-thiazolone III-g, 100 mg of 5A molecular sieve and 0.02 mmol of chiral catalyst D into a dry test tube. Then, add 2.0 mL of dichloromethane, wherein the reaction is carried out at room temperature under the argon protection. After the reaction is completed, the crude product is separated and purified by column chromatography to obtain compound I-ag.

(102) Yellow solid; 83% yield; >20:1 dr, 81% ee; m.p. 134.3-135.1 C., [].sub.D.sup.25=86.6 (c 0.5, CH.sub.2Cl.sub.2).

(103) Wherein, the ee value is determined by HPLC method: Chiralpak IC column; mobile phase 90/10 hexane/EtOH; flow rate: 1.0 mL/min; detection wavelength =220 nm; t.sub.major=24.80 min, t.sub.minor=14.80 min.

(104) Structure identification: .sup.1H NMR (300 MHz, DMSO-d.sub.6) 10.23 (s, 1H), 7.94-7.80 (m, 1H), 7.47 (d, J=7.5 Hz, 1H), 7.43-7.35 (m, 1H), 7.24-7.09 (m, 2H), 6.85 (d, J=3.5 Hz, 1H), 6.60 (dd, J=3.5, 1.8 Hz, 1H), 4.81 (s, 1H), 1.57 (s, 3H). .sup.13C NMR (75 MHz, DMSO-d.sub.6) 175.3, 160.2, 145.2, 142.3, 130.4, 126.1, 125.1, 123.1, 123.0, 111.4, 111.2, 110.4, 75.9, 63.1, 58.9, 11.9. HRMS (ESI-TOF) Calcd. for C.sub.16H.sub.12N.sub.2O.sub.5S [M+Na].sup.+: 367.0359; found: 367.0360.

Example 19: Synthetic Compound I-ah

(105) ##STR00025##

(106) Add 0.2 mmol of 2-nitrobenzofuran II-a, 0.26 mmol of 5H-thiazolone III-h, 100 mg of 5A molecular sieve and 0.02 mmol of chiral catalyst D into a dry test tube. Then, add 2.0 mL of dichloromethane, wherein the reaction is carried out at room temperature under the argon protection. After the reaction is completed, the crude product is separated and purified by column chromatography to obtain compound I-ah.

(107) White solid; 75% yield; >20:1 dr, 80% ee; m.p. 221.9-222.7 C., [].sub.D.sup.25=60.3 (c 0.5, CH.sub.2Cl.sub.2).

(108) Wherein, the ee value is determined by HPLC method: Chiralpak IC column; mobile phase 90/10 hexane/EtOH; flow rate: 1.0 mL/min; detection wavelength =220 nm; t.sub.major=19.62 min, t.sub.minor=16.90 min.

(109) Structure identification: .sup.1H NMR (400 MHZ, DMSO-d.sub.6) 10.19 (s, 1H), 8.62-8.55 (m, 1H), 8.13-8.02 (m, 2H), 7.92-7.83 (m, 1H), 7.78-7.66 (m, 2H), 7.55-7.48 (m, 1H), 7.44-7.35 (m, 1H), 7.20-7.12 (m, 2H), 4.86 (s, 1H), 1.64 (s, 3H). .sup.13C NMR (101 MHz, DMSO-d.sub.6) 176.0, 160.6, 149.0, 146.8, 138.3, 131.2, 130.8, 129.5, 128.5, 128.4, 128.3, 126.6, 125.8, 123.7, 123.4, 119.9, 110.9, 83.4, 63.5, 60.0, 12.5. HRMS (ESI-TOF) Calcd. for C.sub.21H.sub.16N.sub.2O.sub.4S.sub.2 [M+H].sup.+: 406.0856; found: 406.0864.

Example 20: Synthetic Compound I-ai

(110) ##STR00026##

(111) Add 0.2 mmol of 2-nitrobenzofuran II-a, 0.26 mmol of 5H-thiazolone III-i, 100 mg of 5A molecular sieve and 0.02 mmol of chiral catalyst D into a dry test tube. Then, add 2.0 mL of dichloromethane, wherein the reaction is carried out at room temperature under the argon protection. After the reaction is completed, the crude product is separated and purified by column chromatography to obtain compound I-ai.

(112) White solid; 70% yield; >20:1 dr, 82% ee; m.p. 182.6-183.5 C., [].sub.D.sup.25=113.2 (c 0.5, CH.sub.2Cl.sub.2).

(113) Wherein, the ee value is determined by HPLC method: Chiralpak IC column; mobile phase 90/10 hexane/EtOH; flow rate: 1.0 mL/min; detection wavelength =220 nm; t.sub.major=35.00 min, t.sub.minor=28.40 min.

(114) Structure identification: .sup.1H NMR (300 MHz, DMSO-d.sub.6) 10.14 (s, 1H), 8.69-8.61 (m, 1H), 8.05-7.93 (m, 1H), 7.56 (dd, J=8.2, 4.2 Hz, 2H), 7.47 (d, J=7.5 Hz, 1H), 7.42-7.31 (m, 1H), 7.13 (dd, J=8.0, 5.7 Hz, 2H), 4.77 (s, 1H), 1.59 (s, 3H). .sup.13C NMR (101 MHz, DMSO-d.sub.6) 176.2, 160.6, 149.6, 148.5, 137.9, 130.7, 126.5, 125.7, 125.6, 123.8, 123.3, 123.0, 110.8, 83.5, 62.9, 60.1, 12.4. HRMS (ESI-TOF) Calcd. for C.sub.17H.sub.14N.sub.3O.sub.4S [M+H].sup.+: 356.0700; found: 356.0694.

(115) The embodiments of the present invention as described above is exemplary only and not intended to be limiting the present invention. All modifications, equivalent replacements and improvements made within the spirit and scope of the present invention shall be encompassed in the protection scope of the present invention.