Asymmetric hydrogenation of quinolinones or 4-substituted coumarins

Abstract

The present invention relates to the technical field of organic chemistry, specifically to an asymmetric hydrogenation reaction of quinolinones or 4-substituted coumarin compounds. The scheme is as follows: #imgabs0# wherein R 1 is alkyl, aryl; R 2 is hydrogen, methoxy or bromine; X is NR 3 or O; R 3 is hydrogen or alkyl; wherein M is an iridium-phosphine aminopyridine complex having the following structure: #imgabs1# wherein Ar is 3,5-di-tert-butylphenyl.

Description

Technical Field

[0001] The present invention relates to the technical field of ligand chemistry, and in particular to an asymmetric hydrogenation reaction of quinolinone or 4-substituted coumarin compounds. Background Art

[0002] Iridium-phosphine aminopyridine complexes having the following structures have been reported in patent documents such as ZL201010550836.0, etc., which are not listed here one by one;

[0003]

[0004] The above patent document further uses the iridium-phosphine aminopyridine complex to perform chiral catalysis on a series of compounds with the following structures:

[0005] wait.

[0006] By summarizing the above series of reaction formulas, it can be seen that the iridium-phosphine aminopyridine complex is a chiral catalyst, and its suitable substrates are most carbonyl compounds.

[0007] Given the important role of asymmetric hydrogenation reactions in organic synthesis, it is necessary to not be limited to these existing substrate structures, but to try new substrates and develop new processes so that quinolinones and 4-substituted coumarins can also be catalytically hydrogenated with high yield and high selectivity to prepare more chiral products that are useful in further pharmaceutical applications. Summary of the Invention

[0008] In order to expand the reaction substrates and prepare more chiral products useful in pharmaceutical applications, the present invention provides the following technical solutions:

[0009]

[0010] where R 1 is alkyl, aryl; R 2 is hydrogen, methoxy or bromine; X is NR 3 or O; R 3 is hydrogen or alkyl;

[0011] Wherein M is an iridium-phosphine aminopyridine complex having the following structure:

[0012] Wherein Ar is 3,5-di-tert-butylphenyl.

[0013] Furthermore, the technical solution of the present invention includes the following asymmetric catalytic hydrogenation process, which is to prepare the compound of formula 5 by asymmetric catalytic hydrogenation of the compound of formula 4.

[0014]

[0015] Wherein, the definition of M is the same as above. 1 is alkyl, aryl; R 2 is hydrogen, methoxy or bromine.

[0016] Preferably, the compound of formula 5 includes the following compounds,

[0017]

[0018] or preparing the compound of formula 3 by asymmetric catalytic hydrogenation of the compound of formula 2,

[0019]

[0020] Wherein, the definition of M is the same as above. 1 is alkyl, aryl; R 2 is hydrogen, methoxy or bromine; R 3 is hydrogen or alkyl.

[0021] Preferably, the compound of formula 3 includes the following compounds,

[0022]

[0023] In the above asymmetric hydrogenation reaction, the base is an organic base or an inorganic base. The organic base may be triethylamine, diisopropylethylamine, N-methylmorpholine, DBU, etc.; the inorganic base may be sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium tert-butoxide, or potassium tert-butoxide, etc.

[0024] The molar ratio of the base to the substrate compound of formula 2 is (0.01-1.5):1.

[0025] The molar ratio of the base to the substrate compound of formula 4 is (0.01-1.5):1.

[0026] The asymmetric hydrogenation reaction of the present invention is specifically as follows: under nitrogen protection, the hydrogen pressure is 0.5-10 MPa, the amount of base is 1.0-3.0 molar equivalents, and the compound of formula 2 is catalyzed by 0.00001-0.01 molar equivalents of iridium-phosphinopyridine complex (M) in an organic solvent to prepare the compound of formula 3.

[0027] The asymmetric hydrogenation reaction of the present invention is specifically as follows: under nitrogen protection, the hydrogen pressure is 0.5-10 MPa, the amount of base is 1.0-3.0 molar equivalents, and the compound of formula 4 is catalyzed by 0.00001-0.01 molar equivalents of iridium-phosphinopyridine complex (M) in an organic solvent to obtain the compound of formula 5.

[0028] The asymmetric hydrogenation reaction of the present invention is specifically as follows: under nitrogen protection, the hydrogen pressure is 0.5-10 MPa, the amount of base is 1.0-3.0 molar equivalents, and the compound of formula 2 is catalyzed by 0.00001-0.01 molar equivalents of iridium-phosphinopyridine complex (M) in an organic solvent to prepare the compound of formula 3.

[0029] The asymmetric hydrogenation reaction of the present invention is specifically as follows: under nitrogen protection, the hydrogen pressure is 0.5-10 MPa, the amount of base is 1.0-3.0 molar equivalents, and in an organic solvent, the compound of formula 4 is catalyzed by 0.00001-0.01 molar equivalents of iridium-phosphinopyridine complex (M) to prepare the compound of formula 5.

[0030] In the above asymmetric hydrogenation reaction, the solvent is selected from methanol, ethanol, propanol, isopropanol, tetrahydrofuran, toluene, methyl tert-butyl ether, dioxane, DMF and the like.

[0031] The 4-substituted coumarin compounds of the present invention can be used to prepare the new clinical drug R-106578. The reaction formula is as follows:

[0032]

[0033] The quinolinone compounds of the present invention can be used to prepare the new clinical drug MPR3160, and the reaction formula is as follows:

[0034]

[0035] In the asymmetric hydrogenation process of the present invention, the carbonyl groups of quinolinones and 4-substituted coumarin compounds are not reduced, but rather the tetrasubstituted carbon-carbon double bonds are reduced. Due to the unique functional group structure of the substrate, the asymmetric hydrogenation reaction possesses unique advantages and effects, possessing substantial features and significant advancements not previously reported or demonstrated in the prior art. This invention is the result of the inventors' creative efforts. DETAILED DESCRIPTION

[0036] In order to better understand the content of the present invention, further description is given below in conjunction with specific embodiments, but the specific implementation methods are not intended to limit the content of the present invention.

[0037] Example 1:

[0038]

[0039] Under a nitrogen atmosphere, compound 2a (245 mg, 1.0 mmol) was weighed into a 20 mL hydrogenation kettle. A solution of iridium catalyst (R)-1b (2.7 mg, 0.002 mmol) in ethanol (1.0 mL) and a mixed solution of potassium tert-butoxide (44.8 mg, 0.4 mmol) in ethanol (1.0 mL) and toluene (0.5 mL) were then added in sequence. After the additions were complete, the kettle was sealed and pressurized with hydrogen to 5 atm, then released. This process was repeated three times, after which the kettle was filled with hydrogen to 50 atm and stirred at room temperature (25-30°C). The reaction was continued until the pressure in the kettle ceased to decrease (reaction time: 22 hours), after which the pressure was released and the kettle was opened. The reaction solution was filtered through a short silica gel column, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (petroleum ether:ethyl acetate = 2:1) to afford 235 mg of (3a) as a colorless oil. The reaction yield was 95%, the product ee value was 99%, and the tran / cis ratio was 7:1. 1 H NMR(400MHz, CDCl3)δ:7.26(td,J=7.8,1.6Hz,1H),7.24–7.14(m,1H),7.03(d,J=23.4Hz ,2H),4.22–3.99(m,2H),3.66–3.28(m,5H),1.30(d,J=6.7Hz,3H),1.14(t,J=7.1Hz,3H); 13 C NMR(101MHz, CDCl3)δ:169.1,166.0,138.7,128.6,127.8,126.7,123.4,114.9,61.3,55.1,33.9,29.7,18.5,14.0.HRMS(ESI)m / z:[M+H] + calcd for C 14 H 18 NO3 248.1281; Found 248.1286. HPLC analysis (Chiralpak OD-H column, hexane:isopropanol=90:10; flow rate=1mL / min; UVdetection at 254nm):t R (minor) = 6.8min; t R (major)=7.7min(ee value was determined by decarboxylation to 1-methyl-4-phenyl-3,4-dihydroquinolin-2(1H)-one).

[0040] Example 2:

[0041]

[0042] Under a nitrogen atmosphere, compound 2b (259 mg, 1.0 mmol) was weighed into a 20 mL hydrogenation kettle. A solution of iridium catalyst (R)-1b (2.7 mg, 0.002 mmol) in ethanol (1.0 mL) and a mixed solution of potassium tert-butoxide (44.8 mg, 0.4 mmol) in ethanol (1.0 mL) and toluene (0.5 mL) were then added in sequence. After the additions were complete, the kettle was sealed and pressurized with hydrogen to 5 atm, then the pressure was released. This process was repeated three times, after which the kettle was filled with hydrogen to 50 atm and stirred at room temperature (25-30°C). The reaction was continued until the pressure in the kettle ceased to decrease (22 hours), after which the pressure was released and the kettle was opened. The reaction solution was filtered through a short silica gel column, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (petroleum ether:ethyl acetate = 5:1) to yield 245 mg of (3b) as a colorless oil. The reaction yield was 94%, the product ee was 99%, and the tran / cis ratio was 11:1. 1 H NMR(400MHz, CDCl3)δ:7.36–7.22(m,1H),7.21–7.10(m,1H),7.09–6.74(m,2H),4.21–3.83(m,2H),3.62(d,J=2.4Hz, 1H),3.41(s,3H),3.14(ddd,J=8.8,6.8,2.6Hz,1H),2.10–1.41(m,2H),1.03(t,J=7.2Hz,3H),0.94(t,J=7.4Hz,3H); 13 C NMR (101MHz, CDCl3) δ: 169.1, 165.8, 138.9, 128.7, 127.9, 127.0, 123.0, 115.0, 61.4, 53.3, 42.0, 29.7, 26.6, 13.9, 11.4; HRMS (ESI) m / z: [M+Na] + calcd for C 15 H 19 NO3Na 284.1257; Found 284.1262. HPLC analysis (Chiralpak AD-H column, hexane:isopropanol=95:5; flow rate=1mL / min; UV detection at 210nm): t1=9.1min (minor); t2=9.9min (major); t3=10.9min (minor); t4=11.5min (minor).

[0043] Example 3:

[0044]

[0045] Under a nitrogen atmosphere, compound 2c (273 mg, 1.0 mmol) was weighed into a 20 mL hydrogenation kettle. A solution of iridium catalyst (R)-1b (2.7 mg, 0.002 mmol) in ethanol (1.0 mL) and a mixed solution of potassium tert-butoxide (44.8 mg, 0.4 mmol) in ethanol (1.0 mL) and toluene (0.5 mL) were then added in sequence. After the additions were complete, the kettle was sealed and pressurized with hydrogen to 5 atm, then released. This process was repeated three times. The kettle was then filled with hydrogen to 50 atm and stirred at room temperature (25-30°C). The reaction was continued until the pressure in the kettle ceased to decrease (22 hours), after which the pressure was released and the kettle was opened. The reaction solution was filtered through a short silica gel column. The filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (petroleum ether:ethyl acetate = 5:1) to yield 258 mg of (3c) as a colorless oil. The reaction yield was 94%, the product ee was 99%, and the tran / cis ratio was 12:1. 1 H NMR(400MHz, CDCl3)δ:7.34–7.20(m,1H),7.21–7.09(m,1H),7.09–6.77(m,2H),4.25–3.85(m,2H),3.60(d,J=2.0Hz,1 H),3.42(s,3H),3.29–3.03(m,1H),1.74–1.45(m,2H),1.45–1.22(m,2H),1.03(t,J=7.0Hz,3H),0.90(t,J=7.2Hz,3H); 13 C NMR(101MHz, CDCl3)δ:169.0,165.7,138.8,128.5,127.8,127.2,123.0,115.0,61.3,53.4,40.2,35.7,29.6,20.0,13.8,13.8; HRMS(ESI)m / z:[M+H] + calcdfor C 16 H 22 NO3 276.1594; Found 276.1599. HPLC analysis (Chiralpak AS-H column, hexane:isopropanol=90:10; flow rate=1mL / min; UV detection at 210nm): t1=8.7min(major); t2=13.5min(minor); t3=15.3min(minor); t4=16.6min(minor).

[0046] Example 4:

[0047]

[0048] Under a nitrogen atmosphere, compound 2d (287 mg, 1.0 mmol) was weighed into a 20 mL hydrogenation kettle. A solution of iridium catalyst (R)-1b (2.7 mg, 0.002 mmol) in ethanol (1.0 mL) and a mixed solution of potassium tert-butoxide (44.8 mg, 0.4 mmol) in ethanol (1.0 mL) and toluene (0.5 mL) were then added in sequence. After the additions were complete, the kettle was sealed and pressurized with hydrogen to 5 atm, then released. This process was repeated three times. The kettle was then filled with hydrogen to 50 atm and stirred at room temperature (25-30°C). The reaction was continued until the pressure in the kettle ceased to decrease (24 hours), after which the pressure was released and the kettle was opened. The reaction solution was filtered through a short silica gel column. The filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (petroleum ether:ethyl acetate = 2:1) to afford 271 mg of compound 3d as a colorless oil. The reaction yield was 94%, the product ee was 99%, and the tran / cis ratio was 11:1. 1 H NMR(400MHz, CDCl3)δ:7.25(t,J=7.8Hz,1H),7.13(d,J=7.5Hz,1H),7.08–6.89(m,2H),4.25–3.84(m,2H),3.57(d,J=4.4Hz, 1H),3.42(s,3H),3.33(t,J=7.8Hz,1H),1.86–1.50(m,1H),1.39(t,J=7.4Hz,2H),1.18–0.94(m,6H),0.90(d,J=6.8Hz,3H); 13 C NMR (101MHz, CDCl3) δ: 169.0, 165.7, 138.9, 128.3, 127.8, 127.6, 123.1, 115.1, 61.4, 53.3, 42.7, 38.3, 29.7, 24.9, 22.5, 13.9; HRMS (ESI) m / z: [M+H] + calcd for C 17 H 24 NO3 290.1751; Found 290.1754. HPLC analysis (Chiralpak AD-H column, hexane:isopropanol=95:5; flow rate=1mL / min; UVdetection at 210nm):t R =5.7min(major); t R=6.0min(minor)(ee value was testedafter decarboxylation of its 3-position ester group).

[0049] Example 5:

[0050]

[0051] Under a nitrogen atmosphere, compound 2e (321 mg, 1.0 mmol) was weighed into a 20 mL hydrogenation kettle. A solution of iridium catalyst (R)-1b (2.7 mg, 0.002 mmol) in ethanol (1.0 mL) and a mixed solution of potassium tert-butoxide (44.8 mg, 0.4 mmol) in ethanol (1.0 mL) and toluene (0.5 mL) were then added in sequence. After the additions were complete, the kettle was sealed and pressurized with hydrogen to 5 atm, then released. This process was repeated three times, after which the kettle was filled with hydrogen to 50 atm and stirred at room temperature (25-30°C). The reaction was continued until the pressure in the kettle ceased to decrease (48 hours), after which the pressure was released and the kettle was opened. The reaction solution was filtered through a short silica gel column, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (petroleum ether:ethyl acetate = 2:1) to yield 306 mg (3e) as a colorless oil. The reaction yield was 95%, the product ee was 99%, and the tran / cis ratio was 18:1. 1 H NMR(400MHz, CDCl3)δ:7.34–7.13(m,4H),7.12–6.85(m,5H),4.06–3.85(m,2H),3.60(d,J=1.7Hz,1 H),3.51(t,J=8.5Hz,1H),3.39(s,3H),2.92–2.80(m,1H),2.80–2.57(m,1H),0.97(t,J=7.1Hz,3H); 13 C NMR(101MHz, CDCl3)δ:168.9,165.2,139.0,137.8,129.4,128.7,128.5,128.1,12 6.7,126.6,123.2,115.0,61.4,52.3,42.5,40.5,29.7,13.9; HRMS(ESI)m / z:[M+H] + calcd for C 20 H 22NO3324.1594; Found 324.1593. HPLC analysis (Chiralpak OD-H column, hexane:isopropanol=90:10; flow rate=1mL / min; UV detection at 210nm):t R (minor) = 9.6min; t R (major)=10.7min(ee value was tested after decarboxylation of its 3-position ester group).

[0052] Example 6:

[0053]

[0054] Under a nitrogen atmosphere, compound 2f (335 mg, 1.0 mmol) was weighed into a 20 mL hydrogenation kettle. A solution of iridium catalyst (R)-1b (2.7 mg, 0.002 mmol) in ethanol (1.0 mL) and a mixed solution of potassium tert-butoxide (44.8 mg, 0.4 mmol) in ethanol (1.0 mL) and toluene (0.5 mL) were then added in sequence. After the additions were complete, the kettle was sealed and pressurized with hydrogen to 5 atm, then released. This process was repeated three times, after which the kettle was filled with hydrogen to 50 atm and stirred at room temperature (25-30°C). The reaction was continued until the pressure in the kettle ceased to decrease (reacting for 24 hours), after which the pressure was released and the kettle was opened. The reaction solution was filtered through a short silica gel column, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (petroleum ether:ethyl acetate = 2:1) to yield 320 mg (3f) as a colorless oil. The reaction yield was 95%, the product ee was 99%, and the tran / cis ratio was 11:1. 1 H NMR(400MHz, CDCl3)δ:7.40–7.31(m,3H),7.31–7.18(m,4H),7.12(t,J=7.3Hz,2H),4.11(d,J=39.9Hz,2H),3.79( d,J=2.3Hz,1H),3.49(s,3H),3.41(t,J=8.4Hz,1H),2.91–2.47(m,2H),2.33–1.78(m,2H),1.11(t,J=7.1Hz,3H); 13C NMR(101MHz, CDCl3)δ:168.9,165.6,141.0,139.0,128.7,128.5,128.3,128.0,126.9 ,126.1,123.2,115.1,61.5,53.4,40.0,35.1,32.9,29.8,13.9; HRMS(ESI)m / z:[M+H] + calcd for C 21 H 24 NO3 338.1751; Found 338.1756. HPLC analysis (Chiralpak AD-H column, hexane:isopropanol=90:10; flow rate=1mL / min; UV detection at 210nm):t R (minor) = 6.5min; t R (major)=7.0min(ee value was tested after decarboxylation of its 3-position ester group).

[0055] Example 7:

[0056]

[0057] Under a nitrogen atmosphere, compound 2g (301mg, 1.0mmol) was weighed into a 20mL hydrogenation kettle. A solution of iridium catalyst (R)-1b (2.7mg, 0.002mmol) in ethanol (1.0mL) and a mixed solution of potassium tert-butoxide (44.8mg, 0.4mmol) in ethanol (1.0mL) and toluene (0.5mL) were then added in sequence. After the additions were completed, the kettle was sealed and pressurized with hydrogen to 5atm, then released. This process was repeated three times. The kettle was then filled with hydrogen to 50atm and stirred at room temperature (25-30°C). The reaction was continued until the pressure in the kettle ceased to decrease (24 hours), after which the pressure was released and the kettle was opened. The reaction solution was filtered through a short silica gel column. The filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (petroleum ether:ethyl acetate = 2:1) to yield 288mg (3g) of a colorless oily liquid. The reaction yield was 95%, the product ee was 99%, and the tran / cis ratio was 14:1. 11H NMR (400 MHz, CDCl3) δ: 7.30–7.23 (m, 1H), 7.13 (d, J = 6.7 Hz, 1H), 7.02 (t, J = 7.3 Hz, 2H), 4.17–3.92 (m, 2H), 3.60 (d, J = 2.3 Hz, 1H), 3.42 (s, 3H), 3.22 (t, J = 7.5 Hz, 1H), 1.60–1.46 (m, 2H), 1.44–1.20 (m, 6H), 1.03 (t, J = 7.1 Hz, 3H), 0.86 (t, J = 6.5 Hz, 3H); 13 13C NMR (101 MHz, CDCl3) δ: 169.1, 165.8, 138.9, 128.6, 127.8, 127.4, 123.1, 115.0, 61.4, 53.5, 40.5, 33.6, 31.6, 29.7, 26.5, 22.5, 14.0, 13.9; HRMS (ESI) m / z: [M+Na] + calcd for C 18 H 25 NO3Na 326.1727; Found 326.1730. HPLC analysis (Chiralpak OD-H column, hexane:isopropanol = 90:10; flow rate = 1 mL / min; UV detection at 210 nm): t R (major) = 5.5 min; t R (minor) = 6.0 min (ee value was tested after decarboxylation of its 3-position ester group).

[0058] Example 8:

[0059]

[0060] Under a nitrogen atmosphere, compound 2h (271 mg, 1.0 mmol) was weighed into a 20 mL hydrogenation kettle. A solution of iridium catalyst (R)-1a (2.0 mg, 0.002 mmol) in ethanol (1.0 mL) and a mixed solution of potassium tert-butoxide (44.8 mg, 0.4 mmol) in ethanol (1.0 mL) and toluene (0.5 mL) were then added in sequence. After the additions were complete, the kettle was sealed and pressurized with hydrogen to 5 atm, then released. This process was repeated three times, after which the kettle was filled with hydrogen to 50 atm and stirred at room temperature (25-30°C). The reaction was continued until the pressure in the kettle ceased to decrease (48 hours), after which the pressure was released and the kettle was opened. The reaction solution was filtered through a short silica gel column, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (petroleum ether:ethyl acetate = 2:1) to yield 144 mg (3 h) of a colorless oily liquid. The reaction yield was 53%, the product ee was 94%, and the tran / cis ratio was 10:1. 1 H NMR(400MHz, CDCl3)δ:7.35–7.25(m,2H),7.14–6.98(m,2H),4.17–3.97(m,2H),3.68(d,J=5.2Hz,1H),3.42(s, 3H),2.62–2.34(m,1H),1.11(t,J=7.1Hz,3H),0.97–0.85(m,1H),0.58(d,J=8.0Hz,2H),0.32(d,J=4.5Hz,2H); 13 C NMR (101MHz, CDCl3) δ: 169.1, 166.2, 139.0, 128.1, 127.9, 126.9, 123.3, 114.9, 61.4, 54.5, 44.3, 29.8, 14.7, 14.0, 4.5, 3.8; HRMS (ESI) m / z: [M+Na] + calcd for C 16 H 19 NO3Na 296.1257; Found 296.1260. HPLC analysis (Chiralpak AS-H column, hexane:isopropanol=90:10; flow rate=1mL / min; UV detection at 210nm): t1=13.0min(major); t2=15.1min(minor); t3=17.4min(minor); t4=19.0min(minor).

[0061] Example 9:

[0062]

[0063] Under a nitrogen atmosphere, compound 2i (307 mg, 1.0 mmol) was weighed into a 20 mL hydrogenation kettle. A solution of iridium catalyst (R)-1a (2.0 mg, 0.002 mmol) in ethanol (1.0 mL) and a mixed solution of potassium tert-butoxide (44.8 mg, 0.4 mmol) in ethanol (1.0 mL) and toluene (0.5 mL) were then added sequentially. After the additions were complete, the kettle was sealed and pressurized with hydrogen to 5 atm, then released. This process was repeated three times. The kettle was then filled with hydrogen to 50 atm and stirred at room temperature (25-30°C). The reaction was continued until the pressure in the kettle ceased to decrease (48 hours), after which the pressure was released and the kettle was opened. The reaction solution was filtered through a short silica gel column. The filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (petroleum ether:ethyl acetate = 2:1) to yield 102 mg (3S,4R)-3i) as a colorless oil. The reaction yield was 33%, the product ee value was 75%, and tran / cis>20:1. 1 H NMR(400MHz, CDCl3)δ:7.41–7.22(m,4H),7.17(d,J=7.4Hz,2H),7.06(d,J=8.1Hz,1H),6.98(t,J=7.4Hz,1H),6.85(d,J =7.4Hz,1H),4.61(d,J=9.6Hz,1H),4.15–3.97(m,2H),3.90(d,J=9.6Hz,1H),3.42(s,3H),1.03(td,J=7.1,2.0Hz,3H); 13 C NMR(101MHz, CDCl3)δ:168.6,165.9,139.6,138.9,128.9,128.4,128.4,128.3, 127.6,127.4,123.4,115.0,61.4,55.1,44.9,29.9,13.9; HRMS(ESI)m / z:[M+H] + calcd for C 19 H 20 NO3 310.1438; Found 310.1436. HPLC analysis (Chiralpak OD-H column, hexane:isopropanol=90:10; flow rate=1mL / min; UV detection at 254nm):t R (minor) = 18.6min; t R (major)=21.6min.

[0064] Example 10:

[0065]

[0066] Under a nitrogen atmosphere, compound 2j (324 mg, 1.0 mmol) was weighed into a 20 mL hydrogenation kettle. A solution of iridium catalyst (R)-1b (2.7 mg, 0.002 mmol) in ethanol (1.0 mL) and a mixed solution of potassium tert-butoxide (44.8 mg, 0.4 mmol) in ethanol (1.0 mL) and toluene (0.5 mL) were then added in sequence. After the additions were complete, the kettle was sealed and pressurized with hydrogen to 5 atm, then released. This process was repeated three times. The kettle was then filled with hydrogen to 50 atm and stirred at room temperature (25-30°C). The reaction was continued until the pressure in the kettle ceased to decrease (24 hours), after which the pressure was released and the kettle was opened. The reaction solution was filtered through a short silica gel column. The filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (petroleum ether:ethyl acetate = 2:1) to yield 305 mg of (3j) as a colorless oil. The reaction yield was 94%, the product ee was 98%, and the tran / cis ratio was 7:1. 1 H NMR(400MHz, CDCl3)δ:7.37(dd,J=8.8,2.2Hz,1H),7.36–7.23(m,2H),6.90(d,J=8.4H z,1H),4.22–4.04(m,2H),3.48–3.30(m,5H),1.45–1.26(m,3H),1.18(t,J=7.2Hz,3H); 13 C NMR (101MHz, CDCl3) δ: 168.6, 165.5, 138.1, 130.8, 130.6, 129.6, 116.6, 116.1, 61.5, 54.7, 33.8, 29.8, 18.5, 14.0; HRMS (ESI) m / z: [M+H] + calcd for C 14 H 17 BrNO3 326.0386; Found 326.0387. HPLC analysis (ChiralpakAS-H column, hexane:isopropanol=90:10; flow rate=1mL / min; UV detection at254nm): t1=11.4min (major); t2=13.8min (minor); t3=16.9min (minor); t4=24.7min (minor).

[0067] Example 11:

[0068]

[0069] Under a nitrogen atmosphere, compound 2k (275 mg, 1.0 mmol) was weighed into a 20 mL hydrogenation kettle. A solution of iridium catalyst (R)-1a (4.0 mg, 0.004 mmol) in ethanol (1.0 mL) and a mixed solution of potassium tert-butoxide (44.8 mg, 0.4 mmol) in ethanol (1.0 mL) and toluene (0.5 mL) were then added in sequence. After the additions were completed, the kettle was sealed and pressurized with hydrogen to 5 atm, then released. This process was repeated three times. The kettle was then filled with hydrogen to 50 atm and stirred at 50°C. The reaction was continued until the pressure in the kettle ceased to decrease (48 hours), after which the pressure was released and the kettle was opened. The reaction solution was filtered through a short silica gel column. The filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (petroleum ether:ethyl acetate = 2:1) to yield 220 mg (3k) as a colorless oil. The reaction yield was 80%, the product ee was 98%, and the tran / cis ratio was 8:1. 1 H NMR(400MHz, CDCl3)δ:6.94(d,J=9.2Hz,1H),6.83–6.67(m,2H),4.23–3.97(m,2 H),3.81(s,3H),3.65–3.27(m,5H),1.31(d,J=6.4Hz,3H),1.17(t,J=7.2Hz,3H); 13 C NMR (101MHz, CDCl3) δ: 169.2, 165.6, 155.8, 132.5, 130.3, 115.9, 113.2, 112.0, 61.4, 55.5, 55.1, 34.2, 29.9, 18.7, 14.0; HRMS (ESI) m / z: [M+H] + calcdfor C 15 H 20 NO4 278.1387; Found 278.1389. HPLC analysis (Chiralpak OD-3 column, hexane:isopropanol=90:10; flow rate=1mL / min; UV detection at 254nm):t R (minor) = 8.3min; t R (major)=9.4min(ee value was tested after decarboxylation of its3-position ester group).

[0070] Example 12:

[0071]

[0072] Under a nitrogen atmosphere, compound 21 (259 mg, 1.0 mmol) was weighed into a 20 mL hydrogenation kettle. A solution of iridium catalyst (R)-1b (2.7 mg, 0.002 mmol) in ethanol (1.0 mL) and a mixed solution of potassium tert-butoxide (44.8 mg, 0.4 mmol) in ethanol (1.0 mL) and toluene (0.5 mL) were then added in sequence. After the additions were complete, the kettle was sealed and pressurized with hydrogen to 5 atm, then released. This process was repeated three times. The kettle was then filled with hydrogen to 50 atm and stirred at 50°C. The reaction was continued until the pressure in the kettle ceased to decrease (24 hours), after which the pressure was released and the kettle was opened. The reaction solution was filtered through a short silica gel column. The filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (petroleum ether:ethyl acetate = 2:1) to yield 242 mg (3 L) of a colorless oily liquid. The reaction yield was 93%, the product ee was 99%, and the tran / cis ratio was 8:1. 1 H NMR(400MHz, CDCl3)δ:7.32–7.23(m,1H),7.23–7.15(m,1H),7.10–6.99(m,2H),4.21–4.0 3(m,3H),4.03–3.88(m,1H),3.64–3.22(m,2H),1.56–1.22(m,6H),1.12(t,J=7.2Hz,3H); 13 C NMR (101MHz, CDCl3) δ: 169.0, 165.3, 137.7, 128.8, 127.8, 127.2, 123.2, 114.7, 61.2, 55.0, 37.6, 34.3, 18.9, 13.9, 12.3; HRMS (ESI) m / z: [M+H] + calcd for C 15 H 20 NO3 262.1438; Found 262.1443. HPLC analysis (Chiralpak AS-H column, hexane:isopropanol=90:10; flow rate=1mL / min; UV detection at 210nm): t1=8.8min(minor); t2=9.2min(major); t3=10.9min(minor); t4=15.5min(minor).

[0073] Example 13:

[0074]

[0075] Under a nitrogen atmosphere, compound 2m (321 mg, 1.0 mmol) was weighed into a 20 mL hydrogenation kettle. A solution of iridium catalyst (R)-1b (2.7 mg, 0.002 mmol) in ethanol (1.0 mL) and a mixed solution of potassium tert-butoxide (44.8 mg, 0.4 mmol) in ethanol (1.0 mL) and toluene (0.5 mL) were then added in sequence. After the additions were complete, the kettle was sealed and pressurized with hydrogen to 5 atm, then released. This process was repeated three times. The kettle was then filled with hydrogen to 50 atm and stirred at room temperature (25-30°C). The reaction was continued until the pressure in the kettle ceased to decrease (26 hours), after which the pressure was released and the kettle was opened. The reaction solution was filtered through a short silica gel column. The filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (petroleum ether:ethyl acetate = 2:1) to yield 303 mg (3 mL) of a colorless oil. The reaction yield was 94%, the product ee was 93%, and the tran / cis ratio was 8:1. 1 H NMR(400MHz, CDCl3)δ:7.42–7.27(m,4H),7.27–7.21(m,1H),7.19(d,J=7.4Hz,1 H),7.10(t,J=7.8Hz,1H),7.05–6.95(m,1H),6.88(d,J=7.6Hz,1H),5.50(d,J=1 6.0Hz,1H),4.91(d,J=16.4Hz,1H),4.33–3.86(m,2H),3.58(dd,J=4.6,2.0Hz,1 H),3.54–3.14(m,1H),1.33(dd,J=7.2,2.0Hz,3H),1.15(td,J=7.2,2.0Hz,3H); 13 C NMR(101MHz, CDCl3)δ:169.1,166.0,138.4,137.0,128.7,128.7,127.9,127.3,12 7.2,126.5,123.7,115.9,61.6,55.2,46.9,34.8,19.6,14.1; HRMS(ESI)m / z:[M+H] + calcd for C 20 H 22NO3 324.1594; Found 324.1599. HPLC analysis (Chiralpak AS-H column, hexane:isopropanol=90:10; flow rate=1mL / min; UV detection at 210nm): t1=11.5min(major); t2=14.0min(minor); t3=22.2min(minor); t4=24.3min(minor).

[0076] Example 14:

[0077]

[0078] Under a nitrogen atmosphere, compound 2n (307 mg, 1.0 mmol) was weighed into a 20 mL hydrogenation kettle. A solution of iridium catalyst (R)-1a (4.0 mg, 0.004 mmol) in ethanol (1.0 mL) and a mixed solution of potassium tert-butoxide (44.8 mg, 0.4 mmol) in ethanol (1.0 mL) and toluene (0.5 mL) were then added in sequence. After the additions were complete, the kettle was sealed and pressurized with hydrogen to 5 atm, then released. This process was repeated three times, after which the kettle was filled with hydrogen to 50 atm and stirred at room temperature (25-30°C). The reaction was continued until the pressure in the kettle ceased to decrease (48 hours), after which the pressure was released and the kettle was opened. The reaction solution was filtered through a short silica gel column, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (petroleum ether:ethyl acetate = 2:1) to afford 287 mg (3n) as a colorless oil. The reaction yield was 93%, the product ee was 90%, and the tran / cis ratio was 12:1. 1 H NMR(400MHz, CDCl3)δ:7.51(t,J=7.4Hz,2H),7.46–7.36(m,1H),7.34–7.17(m,3H),7.09–6.94(m,2H),6 .37(d,J=7.6Hz,1H),4.26–4.01(m,2H),3.83–3.46(m,2H),1.44(d,J=5.2Hz,3H),1.15(t,J=7.2Hz,3H); 13 C NMR(101MHz, CDCl3)δ:169.0,165.8,139.9,138.1,129.9,128.8,128.4,128.1, 127.6,127.2,123.6,117.2,61.6,55.41,35.0,19.6,14.1; HRMS(ESI)m / z:[M+H] + calcd for C 19 H20 NO3 310.1438; Found 310.1435. HPLC analysis (Chiralpak AD-H column, hexane:isopropanol=90:10; flow rate=1mL / min; UV detection at 210nm):t R (major) = 7.5 min; t R (minor)=8.5min(ee value was tested after decarboxylation of its 3-position ester group).

[0079] Example 15:

[0080]

[0081] Under a nitrogen atmosphere, compound 2o (321 mg, 1.0 mmol) was weighed into a 20 mL hydrogenation kettle. A solution of iridium catalyst (R)-1a (4.0 mg, 0.004 mmol) in ethanol (1.0 mL) and a mixed solution of potassium tert-butoxide (44.8 mg, 0.4 mmol) in ethanol (1.0 mL) and toluene (0.5 mL) were then added in sequence. After the additions were complete, the kettle was sealed and pressurized with hydrogen to 5 atm, then released. This process was repeated three times, after which the kettle was filled with hydrogen to 50 atm and stirred at room temperature (25-30°C). The reaction was continued until the pressure in the kettle ceased to decrease (48 hours), after which the pressure was released and the kettle was opened. The reaction solution was filtered by column chromatography, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (petroleum ether:ethyl acetate = 2:1) to yield 300 mg of (3o) as a colorless oil. The reaction yield was 93%, the product ee was 92%, and the tran / cis ratio was 18:1. 1 H NMR(400MHz, CDCl3)δ:7.52(t,J=7.6Hz,2H),7.43(t,J=7.4Hz,1H),7.34–7.20(m,2H),7.17(dd,J=7.2,1.6Hz,1H)),7.11–6.94(m,2H),6.37(dd,J=8 .0,1.2Hz,1H),4.21–3.99(m,2H),3.73(d,J=2.4Hz,1H),3.26(td,J=7.2,2 .4Hz,1H),1.89–1.66(m,2H),1.10(t,J=7.2Hz,3H),1.04(t,J=7.4Hz,3H); 13CNMR(101MHz, CDCl3)δ:175.1,173.5,137.9,136.9,130.3,130.1,129.2,128.2 ,127.9,126.6,124.8,117.8,49.8,47.3,25.0,22.8,11.9.HRMS(ESI)m / z:[M+H] + calcd for C 20 H 22 NO3 324.1594; Found 324.1594. HPLC analysis (Chiralpak OD-H column, hexane:isopropanol=95:5; flow rate=1mL / min; UV detection at 210nm):t R (major) = 10.1 min; t R (minor)=16.1min(ee value was tested after decarboxylation of its3-position ester group).

[0082] Example 16:

[0083]

[0084] Under a nitrogen atmosphere, compound 2p (231 mg, 1.0 mmol) was weighed into a 20 mL hydrogenation kettle. A solution of iridium catalyst (R)-1b (5.4 mg, 0.004 mmol) in ethanol (1.0 mL) and a mixed solution of potassium tert-butoxide (44.8 mg, 0.4 mmol) in ethanol (1.0 mL) and toluene (0.5 mL) were then added in sequence. After the additions were complete, the kettle was sealed and pressurized with hydrogen to 5 atm, then released. This process was repeated three times. The kettle was then filled with hydrogen to 50 atm and stirred at 50°C. The reaction was continued until the pressure in the kettle ceased to decrease (48 hours), after which the pressure was released and the kettle was opened. The reaction solution was filtered by column chromatography, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (petroleum ether:ethyl acetate = 2:1) to yield 300 mg (3p) as a colorless oil. The reaction yield was 58%, the product ee was 83%, and the tran / cis ratio was 8:1. 1H NMR(400MHz, CDCl3)δ:9.00(s,1H),7.19(t,J=8.4Hz,2H),7.08–6.98(m,1H),6.85(d,J=7.6Hz,1H),4 .27–4.03(m,2H),3.66–3.45(m,1H),3.44–3.36(m,1H),1.34(d,J=6.8Hz,3H),1.19(t,J=7.2Hz,3H); 13 C NMR (101MHz, CDCl3) δ: 168.9, 167.3, 135.6, 127.9, 126.9, 126.8, 123.7, 115.8, 61.6, 54.8, 34.7, 19.2, 14.0; HRMS (ESI) m / z: [M+Na] + calcd for C 13 H 15 NO3Na 256.0944; Found 256.0948.

[0085] Example 17:

[0086]

[0087] Under a nitrogen atmosphere, compound 4a (232 mg, 1.0 mmol) was weighed into a 20 mL hydrogenation kettle. A solution of iridium catalyst (R)-1b (1.3 mg, 0.001 mmol) in ethanol (1.0 mL) and a solution of potassium tert-butoxide (44.8 mg, 0.4 mmol) in ethanol (1.0 mL) were then added sequentially. After the additions were completed, the kettle was sealed and pressurized with hydrogen to 5 atm, then released. This process was repeated three times. The kettle was then filled with hydrogen to 30 atm and stirred at room temperature (25-30°C). The reaction was continued until the pressure in the kettle ceased to decrease (2 hours), after which the pressure was released and the kettle was opened. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate (5.0 mL). NaHCO₃ (84 mg, 1.0 mmol) was added and stirred at room temperature for 1 hour. The mixture was then filtered and concentrated under reduced pressure. The residue was separated by column chromatography (petroleum ether:ethyl acetate = 5:1) to yield 210 mg of (5a) as a colorless oil. The reaction yield was 90%, the product ee value was 95%, and the tran / cis ratio was 7:1. 1H NMR(400MHz, CDCl3)δ:7.35–7.20(m,2H),7.14(td,J=7.6,1.2Hz,1H),7.08(dd,J=8.0,1.2Hz ,1H),4.27–4.06(m,2H),3.80–3.40(m,2H),1.37(d,J=6.8Hz,3H),1.14(t,J=7.2Hz,3H).HPLC Analysis (Chiralpak AS-H column, hexane:isopropanol=95:5; flow rate=1mL / min; UV detection at 210nm): t1=11.0min (major); t2=13.8min (minor); t3=14.1min (major); t2=14.9min (minor).

[0088] Example 18:

[0089]

[0090] Under a nitrogen atmosphere, compound 4b (246 mg, 1.0 mmol) was weighed into a 20 mL hydrogenation kettle. A solution of iridium catalyst (R)-1b (1.3 mg, 0.001 mmol) in ethanol (1.0 mL) and a solution of potassium tert-butoxide (44.8 mg, 0.4 mmol) in ethanol (1.0 mL) were then added sequentially. After the additions were completed, the kettle was sealed and pressurized with hydrogen to 5 atm, then released. This process was repeated three times. The kettle was then filled with hydrogen to 30 atm and stirred at room temperature (25-30°C). The reaction was continued until the pressure in the kettle ceased to decrease (2 hours), after which the pressure was released and the kettle was opened. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate (5.0 mL). NaHCO₃ (84 mg, 1.0 mmol) was added and stirred at room temperature for 1 hour. The mixture was then filtered and concentrated under reduced pressure. The residue was separated by column chromatography (petroleum ether:ethyl acetate = 3:1) to yield 249 mg of (5b) as a colorless oil. The reaction yield was 94%, the product ee value was 97%, and the tran / cis ratio was 12:1. 1H NMR(400MHz, CDCl3)δ:7.34–7.24(m,1H),7.18(dd,J=7.6,1.6Hz,1H),7.15–7.02(m,2H),4.27–3.94(m,2H),3.79(d,J=2.4Hz,1 H),3.28(ddd,J=8.8,6.8,2.4Hz,1H),1.75–1.54(m,2H),1.03(t,J=7.2Hz,3H),0.98(t,J=7.4Hz,3H).HPLCanalysis(Chiralpak AS-H column, hexane:isopropanol=95:5; flow rate=1mL / min; UVdetection at 210nm): t1=9.5min(major); t2=10.7min(minor); t3=11.4min(major); t2=14.8min(minor).

[0091] Example 19:

[0092]

[0093] Under a nitrogen atmosphere, compound 4c (260 mg, 1.0 mmol) was weighed into a 20 mL hydrogenation kettle. A solution of iridium catalyst (R)-1b (1.3 mg, 0.001 mmol) in ethanol (1.0 mL) and a solution of potassium tert-butoxide (44.8 mg, 0.4 mmol) in ethanol (1.0 mL) were then added sequentially. After the additions were complete, the kettle was sealed and pressurized with hydrogen to 5 atm, then released. This process was repeated three times. The kettle was then filled with hydrogen to 30 atm and stirred at room temperature (25-30°C). The reaction was continued until the pressure in the kettle ceased to decrease (2 hours), after which the pressure was released and the kettle was opened. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate (5.0 mL). NaHCO₃ (84 mg, 1.0 mmol) was added and stirred at room temperature for 1 hour. The mixture was then filtered and concentrated under reduced pressure. The residue was separated by column chromatography (petroleum ether:ethyl acetate = 5:1) to afford 253 mg of (5c) as a colorless oil. The reaction yield was 95%, the product ee value was 97%, and the tran / cis ratio was 12:1. 1H NMR (400MHz, CDCl3) δ: 7.36–6.95 (m, 4H), 4.30–3.91 (m, 2H), 3.76 (d, J = 2.4Hz, 1H), 3.37 (t, J = 7. 2Hz,1H),1.67–1.49(m,2H),1.47–1.28(m,2H),1.02(t,J=7.0Hz,3H),0.93(t,J=7.2Hz,3H).HPLC analysis(Chiralpak AD-H column, hexane:isopropanol=95:5; flow rate=1mL / min; UV detection at 210nm):t R (major) = 5.8 min; t R (minor)=6.1min(ee value was tested after decarboxylation of its 3-position ester group).

[0094] Example 20:

[0095]

[0096] Under a nitrogen atmosphere, compound 4d (274 mg, 1.0 mmol) was weighed into a 20 mL hydrogenation kettle. A solution of iridium catalyst (R)-1b (1.3 mg, 0.001 mmol) in ethanol (1.0 mL) and a solution of potassium tert-butoxide (44.8 mg, 0.4 mmol) in ethanol (1.0 mL) were then added sequentially. After the additions were completed, the kettle was sealed and pressurized with hydrogen to 5 atm, then released. This process was repeated three times. The kettle was then filled with hydrogen to 30 atm and stirred at room temperature (25-30°C). The reaction was continued until the pressure in the kettle ceased to decrease (2 hours), after which the pressure was released and the kettle was opened. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate (5.0 mL). NaHCO₃ (84 mg, 1.0 mmol) was added and stirred at room temperature for 1 hour. The mixture was then filtered and concentrated under reduced pressure. The residue was separated by column chromatography (petroleum ether:ethyl acetate = 5:1) to yield 248 mg of (5d) as a colorless oil. The reaction yield was 90%, the product ee value was 97%, and the tran / cis ratio was 15:1. 11H NMR (400 MHz, CDCl3) δ: 7.26 (td, J = 8.0, 1.6 Hz, 1H), 7.17 (dd, J = 7.2, 1.6 Hz, 1H), 7.11 (dd, J = 7.4, 1.0 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 4.23–3.94 (m, 2H), 3.75 (d, J = 2.0 Hz, 1H), 3.46 (td, J = 8.0, 2.0 Hz, 1H), 1.73–1.56 (m, 1H), 1.51–1.37 (m, 2H), 1.11–0.97 (m, 6H), 0.91 (d, J = 6.4 Hz, 3H); 13 13C NMR (101 MHz, CDCl3) δ: 167.1, 164.5, 150.7, 128.7, 128.4, 124.6(2), 117.0, 62.0, 52.0, 43.5, 37.8, 24.9, 22.5, 22.3, 13.7; HRMS (ESI) m / z: [M+Na] + calcd for C 16 H 20 O4Na 299.1254; Found 299.1258. HPLC analysis (Chiralpak OD-H column, hexane:isopropanol = 95:5; flow rate = 1 mL / min; UV detection at 210 nm): t R (major) = 5.6 min; t R (minor) = 6.0 min (ee value was determined by decarboxylation to 4-isobutylchroman-2-one). <​​​​​​Under a nitrogen atmosphere, compound 4e (260 mg, 1.0 mmol) was weighed into a 20 mL hydrogenation kettle. A solution of iridium catalyst (R)-1b (1.3 mg, 0.001 mmol) in ethanol (1.0 mL) and a solution of potassium tert-butoxide (44.8 mg, 0.4 mmol) in ethanol (1.0 mL) were then added sequentially. After the additions were completed, the kettle was sealed and pressurized with hydrogen to 5 atm, then released. This process was repeated three times. The kettle was then filled with hydrogen to 30 atm and stirred at room temperature (25-30°C). The reaction was continued until the pressure in the kettle ceased to decrease (10 hours), after which the pressure was released and the kettle was opened. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate (5.0 mL). NaHCO₃ (84 mg, 1.0 mmol) was added and stirred at room temperature for 1 hour. The mixture was then filtered and concentrated under reduced pressure. The residue was separated by column chromatography (petroleum ether:ethyl acetate = 3:1) to yield 210 mg of (5e) as a colorless oil. The reaction yield was 80%, the product ee value was 74%, and tran / cis>20:1. 1 H NMR (400MHz, CDCl3) δ: 7.20 (ddd, J=8.0, 7.2, 2.0Hz, 1H), 7.08 (dd, J=7.4, 1.8H z,1H),7.04(dd,J=7.6,1.2Hz,1H),7.02–6.97(m,1H),4.03–3.95(m,1H),3.95 –3.86(m,1H),3.84(d,J=2.0Hz,1H),3.01(dd,J=8.0,1.6Hz,1H),1.77–1.64(m ,1H),0.95(d,J=6.8Hz,3H),0.92(t,J=7.2Hz,3H),0.84(d,J=6.4Hz,3H).HPLC analysis(Chiralpak AS-H column, hexane:isopropanol=95:5; flow rate=1mL / min; UVdetection at 210nm):t R (major) = 7.6 min; t R (minor)=9.8min.

[0100] Example 22:

[0101]

[0102] Under nitrogen, compound 4f (300 mg, 1.0 mmol) was weighed into a 20 mL hydrogenation reactor. A solution of iridium catalyst (R)-1b (1.3 mg, 0.001 mmol) in ethanol (1.0 mL) and a solution of potassium tert-butoxide (44.8 mg, 0.4 mmol) in ethanol (1.0 mL) were then added. After the additions were complete, the reactor was sealed and pressurized with hydrogen to 5 atm, then released. This process was repeated three times. The reactor was then filled with hydrogen to 30 atm and stirred at room temperature (25-30°C). The reaction was continued until the pressure in the reactor ceased to decrease (24 hours), after which the pressure was released and the reactor was opened. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate (5.0 mL). NaHCO₃ (84 mg, 1.0 mmol) was added and stirred at room temperature for 1 hour. The mixture was then filtered and concentrated under reduced pressure. The residue was separated by column chromatography (petroleum ether:ethyl acetate = 3:1) to afford 210 mg of (5f) as a colorless oil. The reaction yield was 88%, the product ee value was 19%, and tran / cis>20:1. 1 H NMR(400MHz, CDCl3)δ:7.30–7.24(m,1H),7.16–7.05(m,3H),4.11–3.96(m,2H),3.94(d,J=1.6Hz,1H), 3.12(d,J=8.1Hz,1H),1.89–1.56(m,5H),1.49–1.36(m,1H),1.32–1.01(m,5H),0.99(t,J=7.2Hz,3H); 13 C NMR(101MHz, CDCl3)δ:167.6,165.0,151.0,129.8,128.7,124.2,123.1,116.8,6 2.0,53.5,49.8,46.0,41.2,30.5,29.9,26.0,25.9,13.7; HRMS(ESI)m / z:[M+Na] + calcd for C 18 H 22 O4Na 325.1410; Found 325.1415. HPLC analysis (Chiralpak AD-H column, hexane:isopropanol=90:10; flow rate=1mL / min; UV detection at 220nm):t R (major) = 5.7 min; t R (minor)=6.0min.

[0103] Example 23:

[0104]

[0105] Under a nitrogen atmosphere, compound 4g (308 mg, 1.0 mmol) was weighed into a 20 mL hydrogenation kettle. A solution of iridium catalyst (R)-1b (1.3 mg, 0.001 mmol) in ethanol (1.0 mL) and a solution of potassium tert-butoxide (44.8 mg, 0.4 mmol) in ethanol (1.0 mL) were then added in sequence. After the additions were complete, the kettle was sealed and pressurized with hydrogen to 5 atm, then released. This process was repeated three times. The kettle was then filled with hydrogen to 30 atm and stirred at room temperature (25-30°C). The reaction was continued until the pressure in the kettle ceased to decrease (6 hours), after which the pressure was released and the kettle was opened. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate (5.0 mL). NaHCO₃ (84 mg, 1.0 mmol) was added and stirred at room temperature for 1 hour. The mixture was then filtered and concentrated under reduced pressure. The residue was separated by column chromatography (petroleum ether:ethyl acetate = 5:1) to yield 256 mg (5 g) of a colorless oil. The reaction yield was 93%, the product ee value was 96%, and the tran / cis ratio was 15:1. 1 H NMR(400MHz, CDCl3)δ:7.43–7.23(m,4H),7.17–6.71(m,5H),4.26–3.90(m,2H),3.75(d,J=1.6Hz,1H),3.62(ddd ,J=9.2,7.0,2.2Hz,1H),2.92(dd,J=13.6,7.2Hz,1H),2.77(dd,J=13.6,9.2Hz,1H),0.99(t,J=7.0Hz,3H).HPLC analysis(Chiralpak OD-H column, hexane:isopropanol=95:5; flow rate=1mL / min; UVdetection at 210nm):t R (major) = 12.8 min; t R (minor)=14.52min(ee value was determined by decarboxylation to 4-benzylchroman-2-one).

[0106] Example 24:

[0107]

[0108] Under a nitrogen atmosphere, compound 4h (322 mg, 1.0 mmol) was weighed into a 20 mL hydrogenation kettle. A solution of iridium catalyst (R)-1b (1.3 mg, 0.001 mmol) in ethanol (1.0 mL) and a solution of potassium tert-butoxide (44.8 mg, 0.4 mmol) in ethanol (1.0 mL) were then added sequentially. After the additions were complete, the kettle was sealed and pressurized with hydrogen to 5 atm, then released. This process was repeated three times. The kettle was then filled with hydrogen to 30 atm and stirred at room temperature (25-30°C). The reaction was continued until the pressure in the kettle ceased to decrease (6 hours), after which the pressure was released and the kettle was opened. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate (5.0 mL). NaHCO₃ (84 mg, 1.0 mmol) was added and stirred at room temperature for 1 hour. The mixture was then filtered and concentrated under reduced pressure. The residue was separated by column chromatography (petroleum ether:ethyl acetate = 5:1) to yield 292 mg (5h) of a colorless oil. The reaction yield was 90%, the product ee value was 97%, and the tran / cis ratio was 15:1. 1 H NMR(400MHz, CDCl3)δ:7.36–7.22(m,3H),7.21–6.88(m,6H),4.23–3.95(m,2H),3.82(d,J=2. 0Hz,1H),3.42(t,J=6.8Hz,1H),2.76–2.40(m,2H),2.02–1.80(m,2H),1.01(t,J=7.2Hz,3H); 13 C NMR(101MHz, CDCl3)δ:167.0,164.4,150.8,140.4,128.9,128.7,128.6,128.3,126 .3,124.7,124.0,117.2,62.2,52.0,39.4,35.9,32.8,13.8; HRMS(ESI)m / z:[M+Na] + calcd for C 20 H 20 O4Na 347.1254; Found 347.1258. HPLC analysis (Chiralpak AD-H column, hexane:isopropanol=95:5; flow rate=1mL / min; UVdetection at 210nm):t R (minor) = 9.4min; t R (major)=10.3min(ee value was determined by decarboxylation to 4-phenethylchroman-2-one).

[0109] Example 25:

[0110]

[0111] Under a nitrogen atmosphere, compound 4i (332 mg, 1.0 mmol) was weighed into a 20 mL hydrogenation kettle. A solution of iridium catalyst (R)-1b (1.3 mg, 0.001 mmol) in ethanol (1.0 mL) and a solution of potassium tert-butoxide (44.8 mg, 0.4 mmol) in ethanol (1.0 mL) were then added sequentially. After the additions were complete, the kettle was sealed and pressurized with hydrogen to 5 atm, then released. This process was repeated three times. The kettle was then filled with hydrogen to 30 atm and stirred at room temperature (25-30°C). The reaction was continued until the pressure in the kettle ceased to decrease (4 hours), after which the pressure was released and the kettle was opened. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate (5.0 mL). NaHCO₃ (84 mg, 1.0 mmol) was added and stirred at room temperature for 1 hour. The mixture was then filtered and concentrated under reduced pressure. The residue was separated by column chromatography (petroleum ether:ethyl acetate = 2:1) to yield 292 mg of (5i) as a colorless oil. The reaction yield was 95%, the product ee value was 98%, and the tran / cis ratio was 13:1. 1 H NMR (400MHz, CDCl3) δ: 7.28 (t, J = 7.5Hz, 1H), 7.18 (d, J = 7.2Hz, 1H), 7.15–6.95 (m, 2H), 4.21–3.98 (m, 4H), 3.77 (d, J = 1. 9Hz,1H),3.38(t,J=5.6Hz,1H),2.30(t,J=6.8Hz,2H),1.78–1.54(m,4H),1.24(t,J=7.2Hz,3H),1.03(t,J=7.2Hz,3H); 13 C NMR(101MHz, CDCl3)δ:172.8,166.9,164.4,150.7,128.9,128.7,124.7,123.8,1 17.1,62.2,60.5,52.1,39.7,33.7,33.6,22.0,14.2,13.8; HRMS(ESI)m / z:[M+Na] + calcd for C 18 H 22O6Na 357.1309; Found 357.1315. HPLC analysis (Chiralpak OJ-H column, hexane:isopropanol=90:10; flow rate=1mL / min; UV detection at 210nm):t R (major) = 21.0 min; t R (minor)=23.9min(ee value was determined by decarboxylation to 4-(4-ethoxy-4-oxobutyl)chroman-2-one).

[0112] Example 25:

[0113]

[0114] Under a nitrogen atmosphere, compound 4j (375 mg, 1.0 mmol) was weighed into a 20 mL hydrogenation kettle. A solution of iridium catalyst (R)-1b (1.3 mg, 0.001 mmol) in ethanol (1.0 mL) and a solution of potassium tert-butoxide (44.8 mg, 0.4 mmol) in ethanol (1.0 mL) were then added sequentially. After the additions were complete, the kettle was sealed and pressurized with hydrogen to 5 atm, then released. This process was repeated three times. The kettle was then filled with hydrogen to 30 atm and stirred at room temperature (25-30°C). The reaction was continued until the pressure in the kettle ceased to decrease (6 hours), after which the pressure was released and the kettle was opened. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate (5.0 mL). NaHCO₃ (84 mg, 1.0 mmol) was added and stirred at room temperature for 1 hour. The mixture was then filtered and concentrated under reduced pressure. The residue was separated by column chromatography (petroleum ether:ethyl acetate = 3:1) to yield 354 mg (5 g) of a colorless oil. The reaction yield was 94%, the product ee value was 92%, and the tran / cis ratio was 12:1. 1 H NMR(400MHz, CDCl3)δ:7.44–6.92(m,4H),4.29–3.96(m,2H),3.87(d,J=23.2Hz,1H),3.53– 3.09(m,3H),2.83(s,3H),1.90–1.71(m,2H),1.43(d,J=14.8Hz,9H),1.03(t,J=7.2Hz,3H); 13C NMR(101MHz, CDCl3)δ:166.7,164.2,155.5,150.7,129.0,128.4,124.8,123.9,1 17.1,79.8,62.1,51.8,45.6,37.2,34.0,31.9,28.4,13.8; HRMS(ESI)m / z:[M+Na] + calcd for C 20 H 27 NO6Na 400.1731; Found 400.1735. HPLC analysis (Chiralpak OD-H column, hexane:isopropanol=90:10; flow rate=1mL / min; UVdetection at 210nm): t R (major) = 7.8 min; t R (minor)=8.2min(ee value was determined by decarboxylation to (2-((tert-butoxycarbonyl)(methyl)amino)ethyl)chroman-2-one).

[0115] Example 26:

[0116]

[0117] Under a nitrogen atmosphere, compound 4k (318 mg, 1.0 mmol) was weighed into a 20 mL hydrogenation kettle. A solution of iridium catalyst (R)-1b (1.3 mg, 0.001 mmol) in ethanol (1.0 mL) and a solution of potassium tert-butoxide (44.8 mg, 0.4 mmol) in ethanol (1.0 mL) were then added sequentially. After the additions were completed, the kettle was sealed and pressurized with hydrogen to 5 atm, then released. This process was repeated three times. The kettle was then filled with hydrogen to 30 atm and stirred at room temperature (25-30°C). The reaction was continued until the pressure in the kettle ceased to decrease (3 hours), after which the pressure was released and the kettle was opened. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate (5.0 mL). NaHCO₃ (84 mg, 1.0 mmol) was added and stirred at room temperature for 1 hour. The mixture was then filtered and concentrated under reduced pressure. The residue was separated by column chromatography (petroleum ether:ethyl acetate = 5:1) to yield 294 mg (5k) as a colorless oil. The reaction yield was 92%, the product ee value was 98%, and the tran / cis ratio was 14:1. 11H NMR (400 MHz, CDCl3) δ: 7.05 (d, J = 8.0 Hz, 1H), 6.66 (dd, J = 8.4, 2.0 Hz, 1H), 6.63 (d, J = 2.0 Hz, 1H), 4.15–3.99 (m, 2H), 3.79 (s, 3H), 3.74 (d, J = 2.0 Hz, 1H), 3.30 (t, J = 7.2 Hz, 1H), 1.64–1.46 (m, 2H), 1.38–1.22 (m, 6H), 1.06 (t, J = 7.2 Hz, 3H), 0.86 (t, J = 6.4 Hz, 3H); 13 13C NMR (101 MHz, CDCl3) δ: 167.2, 164.6, 159.9, 151.5, 129.1, 116.1, 110.6, 102.5, 62.0, 55.5, 52.3, 39.3, 34.6, 31.4, 26.2, 22.4, 13.9, 13.8; HRMS (ESI) m / z: [M+Na] + calcd for C 18 H 24 O5Na 343.1516; Found 343.1520. HPLC analysis (Chiralpak OD-H column, hexane:isopropanol = 95:5; flow rate = 1 mL / min; UV detection at 210 nm): t R (minor) = 6.7 min; t R (major) = 7.8 min (ee value was determined by decarboxylation to 7-methoxy-4-pentylchroman-2-one).

[0118] Example 27:

[0119]

[0120] Under a nitrogen atmosphere, compound 41 (258 mg, 1.0 mmol) was weighed into a 20 mL hydrogenation kettle. A solution of iridium catalyst (R)-1b (2.6 mg, 0.002 mmol) in ethanol (1.0 mL) and a solution of potassium tert-butoxide (44.8 mg, 0.4 mmol) in ethanol (1.0 mL) were then added sequentially. After the additions were complete, the kettle was sealed and pressurized with hydrogen to 5 atm, then released. This process was repeated three times. The kettle was then filled with hydrogen to 30 atm and stirred at room temperature (25-30°C). The reaction was continued until the pressure in the kettle ceased to decrease (6 hours), after which the pressure was released and the kettle was opened. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate (5.0 mL). NaHCO₃ (84 mg, 1.0 mmol) was added and stirred at room temperature for 1 hour. The mixture was then filtered and concentrated under reduced pressure. The residue was separated by column chromatography (petroleum ether:ethyl acetate = 5:1) to yield 294 mg (5 L) of a colorless oily liquid. The reaction yield was 87%, the product ee value was 96%, and the tran / cis ratio was 10:1. 1 H NMR(400MHz, CDCl3)δ:7.29(t,J=7.8Hz,2H),7.20–7.01(m,2H),4.20–4.02(m,2H),3.83(d,J=4.8Hz,1H),2 .85(dd,J=8.8,4.8Hz,1H),1.10(t,J=7.0Hz,3H),1.00–0.75(m,1H),0.74–0.54(m,2H),0.41–0.24(m,2H); 13 C NMR (101MHz, CDCl3) δ: 167.2, 164.8, 150.8, 129.0, 128.3, 124.8, 123.3, 116.9, 62.1, 52.9, 43.3, 15.0, 13.8, 4.0, 3.4; HRMS (ESI) m / z: [M+Na] + calcd for C 15 H 16 O4Na 283.0941; Found 283.0945. HPLC analysis (Chiralpak OD-H column, hexane:isopropanol=95:5; flow rate=1mL / min; UVdetection at 210nm):t R (major) = 11.0 min; t R (minor)=12.6min(ee value was determined by decarboxylation to 4-cyclopropylchroman-2-one).

[0121] Example 28:

[0122]

[0123] Under a nitrogen atmosphere, compound 4m (288 mg, 1.0 mmol) was weighed into a 20 mL hydrogenation kettle. A solution of iridium catalyst (R)-1b (2.6 mg, 0.002 mmol) in ethanol (1.0 mL) and a solution of potassium tert-butoxide (44.8 mg, 0.4 mmol) in ethanol (1.0 mL) were then added sequentially. After the additions were completed, the kettle was sealed and pressurized with hydrogen to 5 atm, then released. This process was repeated three times. The kettle was then filled with hydrogen to 30 atm and stirred at room temperature (25-30°C). The reaction was continued until the pressure in the kettle ceased to decrease (6 hours), after which the pressure was released and the kettle was opened. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate (5.0 mL). NaHCO₃ (84 mg, 1.0 mmol) was added and stirred at room temperature for 1 hour. The mixture was then filtered and concentrated under reduced pressure. The residue was separated by column chromatography (petroleum ether:ethyl acetate = 5:1) to yield 264 mg (5 mL) of a colorless oil. The reaction yield was 91%, the product ee value was 96%, and the tran / cis ratio was 11:1. 1 H NMR (400MHz, CDCl3) δ: 7.18 (d, J = 8.4Hz, 1H), 7.04–6.34 (m, 2H), 4.22–4.05 (m, 2H), 3.89–3.74 (m, 4H), 2. 83(dd,J=8.4,4.4Hz,1H),1.13(t,J=7.2Hz,3H),0.95–0.73(m,1H),0.68–0.45(m,2H),0.36–0.22(m,3H); 13 C NMR (101MHz, CDCl3) δ: 167.3, 164.8, 160.1, 151.6, 128.9, 114.9, 110.8, 102.3, 62.1, 55.5, 53.2, 42.6, 15.2, 13.9, 3.8, 3.1; HRMS (ESI) m / z: [M+Na] + calcd for C 16 H 18 O5Na 313.1046; Found 313.1050. HPLC analysis (Chiralpak OD-H column, hexane:isopropanol=90:10; flow rate=1mL / min; UV detection at 220nm):t R (major) = 5.3 min; tR (minor)=5.9min(ee value was determined by decarboxylation to 4-cyclopropyl-7-methoxychroman-2-one).

[0124] Example 29:

[0125]

[0126] Under a nitrogen atmosphere, compound 4n (288 mg, 1.0 mmol) was weighed into a 20 mL hydrogenation kettle. A solution of iridium catalyst (R)-1b (2.6 mg, 0.002 mmol) in ethanol (1.0 mL) and a solution of potassium tert-butoxide (44.8 mg, 0.4 mmol) in ethanol (1.0 mL) were then added sequentially. After the additions were completed, the kettle was sealed and pressurized with hydrogen to 5 atm, then released. This process was repeated three times. The kettle was then filled with hydrogen to 30 atm and stirred at room temperature (25-30°C). The reaction was continued until the pressure in the kettle ceased to decrease (6 hours), after which the pressure was released and the kettle was opened. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate (5.0 mL). NaHCO₃ (84 mg, 1.0 mmol) was added and stirred at room temperature for 1 hour. The mixture was then filtered and concentrated under reduced pressure. The residue was separated by column chromatography (petroleum ether:ethyl acetate = 5:1) to yield 264 mg (5n) as a colorless oil. The reaction yield was 91%, the product ee value was 97%, and the tran / cis ratio was 11:1. 1 H NMR (400MHz, CDCl3) δ: 7.01 (d, J = 8.4Hz, 1H), 6.85–6.78 (m, 2H), 4.20–4.07 (m, 2H), 3.80 (s, 3H), 2.79 ( dd,J=8.8,5.2Hz,1H),1.13(t,J=7.2Hz,3H),0.97–0.86(m,1H),0.68–0.55(m,2H),0.40–0.28(m,2H); 13 C NMR (101MHz, CDCl3) δ: 167.2, 164.9, 156.4, 144.6, 124.4, 117.6, 113.7, 113.5, 62.0, 55.6, 52.9, 43.4, 15.0, 13.9, 4.1, 3.4; HRMS (ESI) m / z: [M+H] + calcd for C 16 H 19O5291.1227; Found 291.1230. HPLC analysis (Chiralpak OD-H column, hexane:isopropanol=95:5; flow rate=1mL / min; UVdetection at 210nm):t R (minor) = 11.2min; t R (major)=13.2min(ee value was determined by decarboxylation to 4-cyclopropyl-6-methoxychroman-2-one).

[0127] Example 30:

[0128]

[0129] Under a nitrogen atmosphere, compound 4o (294 mg, 1.0 mmol) was weighed into a 20 mL hydrogenation kettle. A solution of iridium catalyst (R)-1b (1.3 mg, 0.001 mmol) in ethanol (1.0 mL) and a solution of potassium tert-butoxide (44.8 mg, 0.4 mmol) in ethanol (1.0 mL) were then added sequentially. After the additions were complete, the kettle was sealed and pressurized with hydrogen to 5 atm, then released. This process was repeated three times. The kettle was then filled with hydrogen to 30 atm and stirred at room temperature (25-30°C). The reaction was continued until the pressure in the kettle ceased to decrease (reaction time: 24 hours). The pressure was then released, the kettle was opened, and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (5.0 mL), and NaHCO₃ (84 mg, 1.0 mmol) was added. The mixture was stirred at room temperature for 1 hour. The mixture was then filtered and concentrated under reduced pressure. The residue was separated by column chromatography (petroleum ether:ethyl acetate = 5:1) to yield 223 mg ((3R,4R)-5o) as a colorless oil. The reaction yield was 75%, the product ee value was 73%, and the tran / cis ratio was >20:1. 1H NMR(400MHz, CDCl3)δ:7.40–7.26(m,2H),7.21–7.12(m,3H),7.10(td,J=7.6,1.2Hz,1H),6.95(dt,J=7.6 ,1.2Hz,1H),4.73(d,J=8.0Hz,1H),4.19–4.01(m,1H),3.97(d,J=8.0Hz,1H),1.06(t,J=7.2Hz,3H).HPLC analysis(Chiralpak AD-Hcolumn,hexane:isopropanol=90:10; flow rate=1mL / min; UV detection at 220nm):t R (major) = 9.7 min; t R (minor)=12.3min.

[0130] Example 31:

[0131]

[0132] Under a nitrogen atmosphere, compound 4a (6.96 g, 30.0 mmol) was weighed into a 60 mL hydrogenation kettle. A solution of iridium catalyst (R)-1b (1.36 mg, 0.001 mmol) in ethanol (1.0 mL) and a mixed solution of potassium tert-butoxide (672 mg, 6 mmol) in ethanol (40.0 mL) and toluene (5.0 mL) were then added sequentially. After the additions were complete, the kettle was sealed and pressurized with hydrogen to 5 atm, then released. This process was repeated three times, after which the kettle was filled with hydrogen to 60 atm and stirred at room temperature (25-30°C). The reaction was continued until the pressure in the kettle ceased to decrease (reaction time: 65 hours). The pressure was then released, the kettle was opened, and the solvent removed under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), and NaHCO₃ (840 mg, 10.0 mmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was then filtered and concentrated under reduced pressure, and the residue was separated by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 6.46 g of a colorless oily liquid (5a). The reaction yield was 92%, the product ee value was 95%, and the tran / cis ratio was 7:1.

[0133] Example 32:

[0134]

[0135] Under a nitrogen atmosphere, compound 4k (6.36 g, 20.0 mmol) was weighed into a 60 mL hydrogenation kettle. A solution of iridium catalyst (S)-1b (1.36 mg, 0.001 mmol) in ethanol (1.0 mL) and a mixed solution of potassium tert-butoxide (448 mg, 4.0 mmol) in ethanol (20.0 mL) and toluene (5.0 mL) were then added sequentially. After the additions were complete, the kettle was sealed and pressurized with hydrogen to 5 atm, then released. This process was repeated three times. The kettle was then filled with hydrogen to 60 atm and stirred at room temperature (25-30°C). The reaction was continued until the pressure in the kettle ceased to decrease (60 hours). The pressure was then released, the kettle was opened, and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), and NaHCO₃ (840 mg, 10.0 mmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was then filtered and concentrated under reduced pressure. The residue was separated by column chromatography (petroleum ether:ethyl acetate = 5:1) to yield 6.02 g of (3R,4S)-5k as a colorless oily liquid. The reaction yield was 94%, the product ee value was 98%, and the tran / cis ratio was 14:1.

[0136] Example 33:

[0137]

[0138] (3R,4S)-5k (1.60 g, 5.0 mmol) and NaCl (615 mg, 10.5 mmol) were weighed into a 50 mL round-bottom flask. DMSO (15 mL) and H₂O (90 μL, 5.0 mmol) were then added. The mixture was heated to reflux and allowed to react for 5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with 30 mL of water, and extracted with ethyl acetate (3 × 20 mL). The organic phase was collected, washed with saturated brine (20 mL), and dried over anhydrous MgSO₄. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by column chromatography to yield 1.02 g of compound (S)-6 as a colorless oily liquid, with a reaction yield of 82%. 1 H NMR(400MHz, CDCl3)δ:7.07(d,J=8.4Hz,1H),6.66(dd,J=8.4,2.5Hz,1H),6.59(d,J=2.5Hz,1H),3.78(s,3H),2.97–2.87(m, 1H),2.80(dd,J=16.0,5.6Hz,1H),2.70(dd,J=16.0,4.0Hz,1H),1.62–1.45(m,2H),1.42–1.22(m,6H),0.87(t,J=6.6Hz,3H); 13C NMR (101MHz, CDCl3) δ: 168.4, 159.5, 152.0, 128.3, 118.7, 110.1, 102.5, 55.4, 35.0, 34.8, 34.4, 31.6, 26.3, 22.5, 14.0; HRMS (ESI) m / z: [M+Na] + calcd for C 15 H 20 O3Na 271.1305; Found271.1310.

[0139] Example 34:

[0140]

[0141] (S)-6 (496 mg, 2.0 mmol) and NaOH (645 mg, 16.0 mmol) were weighed into a 50 mL round-bottom flask. THF (24 mL), MeOH (6 mL), and H₂O (6 mL) were then added and stirred at 35°C for 17 hours. After completion of the reaction, the solution was adjusted to pH <2 with dilute hydrochloric acid (1N, 30.0 mL, 30 mmol) at 0°C. The solution was then extracted with ethyl acetate (3 x 20 mL). The organic phase was collected, washed with saturated brine (20 mL), and dried over anhydrous MgSO₄. The filtrate was then filtered and concentrated under reduced pressure. The resulting residue was separated by column chromatography to yield 465 mg of compound (S)-7 as a colorless oily liquid, with a reaction yield of 83%. (lit. 17 98% ee for (S)-isomer). 1 H NMR(400MHz, CDCl3)δ:10.99(s,1H),7.09–6.93(m,1H),6.53–6.35(m,2H),3.79(s,3H),3.77(s,3H) ,3.45–3.33(m,1H),2.69–2.54(m,2H),1.72–1.53(m,2H),1.30–1.12(m,6H),0.83(t,J=6.4Hz,3H).

[0142] Example 35:

[0143]

[0144] To a solution of (3R,4R)-3o (920 mg, 2.8 mmol) in tetrahydrofuran (20 mL) was slowly added 60% NaH (170 mg, 4.3 mmol) as a solid at 0°C. Upon completion of the addition, the reaction was stirred at 0°C for 30 min. Subsequently, MeI (266 μL, 4.27 mmol) was added at 0°C. Upon completion of the addition, the reaction was stirred at room temperature for 2 h. The reaction was quenched by the addition of 5 mL of water, followed by the addition of a solution of KOH (797 mg, 14.2 mmol) in methanol (10 mL). The reaction was stirred at 90°C for 6 h. Heating was discontinued, and after cooling to room temperature, the reaction solution was diluted with 10 mL of water and adjusted to pH <4. The solution was then extracted with ethyl acetate (3 × 20 mL). The organic phase was collected, washed with saturated brine (20 mL), and dried over anhydrous MgSO₄. The mixture was then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was separated by column chromatography (petroleum ether:ethyl acetate = 5:1-1:1) to afford 0.80 g of (3S,4S)-8 as a white solid, melting point: 118-119°C. The reaction yield was 91%, and the trans / cis ratio was >20:1. 1 H NMR(400MHz, CDCl3)δ:13.95(s,1H),7.64–7.44(m,3H),7.32–7.08(m,5H),6.49–6.38(m,1H),3.21 (dd,J=11.2,3.2Hz,1H),1.87–1.73(m,1H),1.53(s,3H),1.52–1.39(m,1H),0.94(t,J=7.0Hz,3H); 13 C NMR(101MHz, CDCl3)δ:175.1,173.5,137.9,136.9,130.3,130.1,129.2,128.2, 127.9,126.6,124.8,117.8,49.8,47.3,25.0,22.8,11.9.HRMS(ESI)m / z:[M+Na] + calcd for C 19 H 19 NO3Na332.1257; Found 332.1261.

[0145] Example 35:

[0146]

[0147] To a solution of (3S,4S)-8 (309 mg, 1.0 mmol) in toluene (4 mL) was added (PhO)2P(O)N3 (320 μL, 1.5 mmol) and Et3N (350 μL, 2.5 mmol) at room temperature. The reaction was allowed to react at room temperature for 2 hours, followed by heating under reflux for 6 hours. After 6 hours, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in a mixture of KOH (560 mg, 10.0 mmol) in THF (4 mL) and water (2 mL), heated to 80°C, and kept warm for 6 hours. Heating was discontinued, and the reaction mixture was cooled to room temperature. The reaction solution was diluted with 10 mL of water and extracted with ethyl acetate (3 × 20 mL). The organic phase was collected, washed with saturated brine (20 mL), and dried over anhydrous MgSO4. The product was then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by column chromatography (dichloromethane:methanol = 10:1) to afford 183 mg of (3S,4S)-9 as a colorless oily liquid. The reaction yield was 91%, and the trans / cis ratio was >20:1. 1 H NMR(400MHz, CDCl3)δ:7.50(t,J=7.6Hz,2H),7.41(t,J=7.4Hz,1H),7.26–7.10(m,3H),7.09–6.90(m,2H),6.35(d,J =7.6Hz,1H),2.65(dd,J=10.6,3.4Hz,1H),2.03–1.84(m,3H),1.50–1.36(m,1H),1.31(s,3H),0.91(t,J=7.2Hz,3H); 13 C NMR(101MHz, CDCl3)δ:175.8,139.7,138.70,129.8,129.8,128.7,128.2,12 8.2,127.2,122.8,117.0,56.4,50.9,26.0,22.3,11.7.HRMS(ESI)m / z:[M+H] + calcd for C 18 H 21 N2O 281.1648; Found 281.1651.

[0148] Example 36:

[0149]

[0150] To a solution of (3S,4S)-9 (309 mg, 1.0 mmol) in dry THF (4 mL) was added BH3·THF (5 mL, 1 M in THF, 5.0 mmol) at room temperature. The mixture was heated under reflux for 3 hours. Subsequently, 6N HCl (10 mL) was slowly added dropwise until hydrogen evolution ceased. The reaction was continued at room temperature for 30 minutes. Subsequently, NaOH (1 M) was added to adjust the pH to 14. After completion of the reaction, the reaction mixture was extracted with dichloromethane (3 × 20 mL). The organic phase was collected, washed with saturated brine (20 mL), and dried over anhydrous MgSO4. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by column chromatography (dichloromethane:methanol = 10:1) to yield 102 mg of MPR3160 as a colorless oily liquid. The reaction yield was 77%, and the trans / cis ratio was >20:1. 1 H NMR(400MHz, CDCl3)δ:7.41–7.30(m,2H),7.26–7.17(m,2H),7.12(tt,J=7.2,1.2H z,1H),7.03(dd,J=7.6,1.6Hz,1H),6.95(ddd,J=8.6,7.4,1.6Hz,1H),6.80–6.56(m ,2H),3.45(d,J=11.2Hz,1H),3.35(dd,J=11.0,1.8Hz,1H),2.39–2.27(m,1H),1.9 6–1.84(m,1H),1.54(s,2H),1.40–1.29(m,1H),1.17(s,3H),1.01(t,J=7.4Hz,3H).

[0151] Although the present invention has been fully described in conjunction with the specific embodiments, it should be noted that various changes and modifications will be apparent to those skilled in the art. Such changes and modifications will be understood to be included within the scope of the invention as defined by the appended claims.

Claims

1. Asymmetric hydrogenation reaction of quinolinone compounds: where R 1 is alkyl, aryl; R 2 is hydrogen, methoxy or bromine; X is NR 3 or O; R 3 is hydrogen or alkyl; Wherein M is an iridium-phosphine aminopyridine complex having the following structure: Wherein Ar is 3,5-di-tert-butylphenyl.

2. The asymmetric hydrogenation reaction according to claim 1, characterized in that The compound of formula 3 is prepared by asymmetric catalytic hydrogenation of the compound of formula 2. Wherein, the definition of M is the same as that in claim 1; R 1 is alkyl, aryl; R 2 is hydrogen, methoxy or bromine; R 3 is hydrogen or alkyl.

3. The asymmetric hydrogenation reaction according to claim 1, characterized in that The compound of formula 5 is prepared by asymmetric catalytic hydrogenation of the compound of formula 4. Wherein, the definition of M is the same as above; R 1 is alkyl, aryl; R 2 is hydrogen, methoxy or bromine.

4. The asymmetric hydrogenation reaction according to claim 2, characterized in that The prepared compound of formula 3 is:

5. The asymmetric hydrogenation reaction according to claim 3, characterized in that The prepared compound of formula 5 is:

6. The asymmetric hydrogenation reaction according to claim 1, 2 or 3, characterized in that The base is an organic base or an inorganic base.

7. The asymmetric hydrogenation reaction according to claim 1 or 2, characterized in that The molar ratio of the base to the substrate compound of formula 2 is (0.01-1.5):

1.

8. The asymmetric hydrogenation reaction according to claim 1 or 3, characterized in that The molar ratio of the base to the substrate compound of formula 4 is (0.01-1.5):

1.

9. The asymmetric hydrogenation reaction according to any one of claims 1, 2 or 3, characterized in that The base is triethylamine, diisopropylethylamine, N-methylmorpholine, DBU, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium tert-butoxide or potassium tert-butoxide.

10. The asymmetric hydrogenation reaction according to claim 1 or 2, characterized in that Under nitrogen protection, a hydrogen pressure of 0.5-10 MPa, and a base dosage of 1.0-3.0 molar equivalents, the compound of formula 2 is catalyzed by 0.00001-0.01 molar equivalents of iridium-phosphinopyridine complex (M) in an organic solvent to prepare the compound of formula 3.

11. The asymmetric hydrogenation reaction according to claim 1 or 3, characterized in that Under nitrogen protection, hydrogen pressure of 0.5-10 MPa, and the amount of base used is 1.0-3.0 molar equivalents. In an organic solvent, the compound of formula 4 is catalyzed by 0.00001-0.01 molar equivalents of iridium-phosphinopyridine complex (M) to obtain the compound of formula 5.

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