Application of asymmetric catalytic hydrogenation kinetic resolution method of racemic beta-aryl ester or lactone in synthesis of chiral drugs and natural products

Abstract

The invention provides an application of a kinetic resolution method for asymmetric catalytic hydrogenation of racemic beta-aryl ester or lactone. According to the method, a chiral Ir-SpiroPAP catalyst is adopted, and obtained chiral gamma-aryl primary alcohol and chiral beta-aryl ester serve as key chiral raw materials to be used for selective enantiomer synthesis of oligomers of tolterodine, methoxydalaninone, AM-1638, AMG-837, fusterodine, enrasentan and resveratrol, and the chiral gamma-aryl primary alcohol and the chiral beta-aryl ester are used for selective enantiomer synthesis of the oligomers of the tolterodine, the methoxydalaninone, the AM-1638, the AMG-837, the fusterodine, the enrasentan and the resveratrol.

Description

Technical Field

[0001] The present invention relates to the technical field of asymmetric synthesis, and in particular to an application of an asymmetric catalytic hydrogenation method of racemic beta-aryl ester or lactone in the synthesis of chiral drugs. Background Art

[0002] Asymmetric hydrogenation of racemic esters using chiral catalysts has emerged as a promising strategy for the synthesis of chiral primary alcohols. Current successes primarily involve the asymmetric hydrogenation of racemic α-substituted esters, yielding β-chiral primary alcohols via dynamic kinetic analysis. There is only one reported case of asymmetric hydrogenation, the asymmetric hydrogenation of a racemic ester (patent document CN104355997 B), which enantioselectively synthesized a chiral primary alcohol with a distal stereocenter from the δ position via kinetic analysis.

[0003] This patent document (CN104355997 B) demonstrates the remarkable efficacy of chiral Ir-SpiroPAP catalyst in catalyzing the asymmetric hydrogenation of racemic δ-hydroxy esters through kinetic analysis, thereby achieving the enantioselective synthesis of chiral 1,5-diols and recovering the chiral δ-hydroxy esters with excellent enantioselectivity.

[0004]

[0005] The chiral γ-aryl primary alcohols and chiral β-aryl esters obtained from the asymmetric hydrogenation reaction can be used as chiral intermediates for the enantioselective synthesis of drugs or natural products. These drugs or natural products may include tolterodine, methoxydalbergiaquinone, AM-1638, AMG-837, fesoterodine, enrasentan, and resveratrol oligomers.

[0006] Tolterodine: Clinically used to treat symptoms such as frequent urination, urgency or urge incontinence caused by overactive bladder.

[0007] Methoxydalbergiaquinone: In pharmacy, it is used as a photosensitizing dye and colorant, and acts as a catalyst in the synthesis of some drugs. In cosmetics, it is used as a fragrance ingredient to impart fragrance to products. It is also used in organic synthesis reactions and in research on organic photochemistry and photosensitization chemistry.

[0008] AM-1638 is a potent and orally bioavailable GPR40 / FFA1 full agonist.

[0009] AMG-837 is a potent, orally bioavailable GPR40 agonist.

[0010] Fesoterodine is an orally active, non-subtype selective, competitive muscarinic receptor (mAChR) antagonist.

[0011] Enrasentan is an endothelin receptor antagonist and an antihypertensive drug.

[0012] Resveratrol is a natural polyphenolic compound that has received widespread attention for its diverse biological activities, including antioxidant, antibacterial, and antitumor properties. Due to the scarcity of natural sources and the high cost of extraction, researchers have begun exploring methods for the artificial synthesis of resveratrol oligomers. Resveratrol oligomers are compounds composed of two or more resveratrol molecules connected by carbon-carbon bonds, and they offer unique advantages in terms of biological activity and stability. However, the low hydrogenation reactivity of esters and the inherent complexity of resolving distant stereocenters have hindered the development of efficient catalytic schemes for the asymmetric hydrogenation of racemic esters containing distant stereocenters via kinetic resolution. Achieving asymmetric hydrogenation of racemic esters with distant stereocenters via kinetic resolution remains a daunting challenge.

[0013] To address this issue, the present invention provides an asymmetric hydrogenation reaction for racemic β-aryl esters or lactones containing a remote benzyl tertiary stereocenter. In the presence of a chiral Ir-SpiroPAP catalyst, the racemic β-aryl ester or lactone is hydrogenated, enhancing chiral recognition through the lactone form. This asymmetric hydrogenation process has been patented in China.

[0014] This time, we further applied for patent protection for its application. Summary of the Invention

[0015] In order to achieve the technical purpose of the present invention, the technical solution provided by the present invention is:

[0016] First, in the presence of a chiral Ir-SpiroPAP catalyst, a racemic β-aryl ester or lactone is hydrogenated, and the obtained chiral γ-aryl primary alcohol and chiral β-aryl ester are further used to prepare drugs and natural products.

[0017] The hydrogenation reaction is described in the previous patent application. It can be performed by asymmetric catalytic hydrogenation of a racemic β-aryl ester or lactone in the presence of an iridium catalyst containing a chiral spirocyclic pyridine aminophosphine ligand and a base to prepare a chiral β-aryl ester and the corresponding chiral γ-aryl primary alcohol:

[0018]

[0019] The racemic β-aryl ester or lactone is preferably a lactone compound, specifically

[0020] X may be hydrogen, alkyl, alkoxy, halogen, or carboxylate.

[0021] Wherein, R can be aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkyl or cyclic alkyl; R 2 For alkyl.

[0022] The asymmetric hydrogenation reaction process of the lactone compound is:

[0023]

[0024] Here, X can be hydrogen, alkyl, alkoxy, halogen or carboxylate.

[0025] Preferably, the reaction formula of the asymmetric catalytic hydrogenation is:

[0026]

[0027] The prepared (R)-3 compound and (S)-2 compound are not disclosed in the prior art.

[0028]

[0029] The prepared (R)-10 compound is not disclosed in the prior art.

[0030]

[0031] The prepared (R)-12 compound is not disclosed in the prior art.

[0032]

[0033] Wherein, the chiral spirocyclic pyridine aminophosphine ligand iridium catalyst structural formula is:

[0034]

[0035] or an enantiomer thereof, wherein Y may be hydrogen or alkyl.

[0036] (R)-4e is preferably:

[0037]

[0038] Or it is the enantiomer (S)-4e catalyst. When the catalyst is (S)-4e, the asymmetric catalytic hydrogenation reaction formula can be:

[0039] The definition of R is the same as above.

[0040] When the catalyst is (S)-4e, the asymmetric catalytic hydrogenation reaction formula can also be:

[0041]

[0042] The above-mentioned asymmetric catalytic hydrogenation reaction is carried out in the presence of a base, wherein the base is an alkali metal salt of an alcohol (such as potassium tert-butoxide, sodium tert-butoxide, potassium isopropoxide, sodium isopropoxide), an alkali metal hydroxide (such as potassium hydroxide, sodium hydroxide), or an alkali metal carbonate (such as potassium carbonate, sodium carbonate), preferably an alkali metal salt of an alcohol.

[0043] The above-mentioned asymmetric catalytic hydrogenation reaction is carried out in the presence of a solvent, wherein the reaction solvent is one of methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, toluene, methyl tert-butyl ether, dioxane, DMF, DMSO or a mixed solvent thereof, preferably an alcohol solvent.

[0044] According to the asymmetric hydrogenation method mentioned above, (S)-3b and (R)-1b were prepared from rac-1b by hydrogenation reaction, and tolterodine was further prepared. The reaction equation is:

[0045]

[0046] According to the asymmetric hydrogenation method mentioned above, rac-1g is subjected to hydrogenation and reduction to obtain (R)-3g, which is further prepared into methoxydalbergiaquinone. The reaction equation is:

[0047]

[0048] The reduction reaction reagent is lithium aluminum hydride or the like.

[0049] The reduction reaction solvent is an ether solvent or the like.

[0050] According to the asymmetric hydrogenation method mentioned above, (S)-16 was obtained from rac-13h through hydrogenation and reduction, and AM-1638 was further prepared. The reaction equation is:

[0051]

[0052] The reduction reaction reagents are pyridine, trifluoromethanesulfonic anhydride, triethylamine, triphenylphosphine and palladium acetate.

[0053] The reduction reaction solvent is dichloromethane or N,N-dimethylformamide.

[0054] According to the asymmetric hydrogenation method mentioned above, (S)-18 is obtained from rac-11p through hydrogenation and reduction reaction, and AMG-837 is further prepared. The reaction equation is:

[0055]

[0056] The reduction reaction reagents are pyridine, trifluoromethanesulfonic anhydride, triethylamine, triphenylphosphine and palladium acetate.

[0057] The reduction reaction solvent is dichloromethane or N,N-dimethylformamide.

[0058] Furthermore, the chiral β-aryl ester with a tertiary benzyl stereocenter in the above hydrogenation reaction is used as a chiral building block to synthesize chiral drugs or natural products.

[0059] Fesoterodine is prepared from (R)-2e through reduction reaction, reductive amination reaction and esterification reaction. The reaction equation is:

[0060]

[0061] The reduction reaction reagent is diisobutylaluminum hydride.

[0062] The reduction reaction solvent is toluene.

[0063] The reductive amination reaction reagent is ( i Pr)2NH, Pd / C and H2.

[0064] The reductive amination reaction solvent is methanol.

[0065] The esterification reagent is i PrCOCl.

[0066] The esterification reaction solvent is triethylamine or dichloromethane.

[0067] Enrasentan is prepared from (S)-2q through Michael addition, intramolecular ring closure reaction, electrophilic substitution reaction and electrophilic substitution reaction. The reaction equation is:

[0068]

[0069] The Michael addition and intramolecular ring closure reaction reagents are piperonal, EtN( i Pr)2 and TiCl4.

[0070] The solvent for the Michael addition and intramolecular ring-closure reactions is dichloromethane.

[0071] The electrophilic substitution reaction reagent is CF3CO2H.

[0072] The electrophilic substitution reaction solvent is dichloromethane.

[0073] The electrophilic substitution reaction reagents are LiOH, K2CO3 and ethylene carbonate.

[0074] The electrophilic substitution reaction solvent is toluene.

[0075] (S)-2p is hydrolyzed and electrophilicly substituted to obtain (S)-24, which is then further prepared to obtain pallidol, (+)-quadragularin A, and (+)-isopaucifloral F. The reaction equation is:

[0076]

[0077] The hydrolysis and electrophilic substitution reaction reagents are KOH and MeI.

[0078] The solvent for the hydrolysis and electrophilic substitution reactions is MeOH.

[0079] The electrophilic substitution reaction reagent is MsOH.

[0080] The electrophilic substitution reaction solvent is N,N-dimethylformamide.

[0081] The present invention uses the obtained chiral γ-aryl primary alcohol or chiral β-aryl ester as a chiral intermediate for the enantioselective synthesis of drugs or natural products, confirming the scalability and practicality of this method. It is a pioneering application with substantial characteristics and significant progress. DETAILED DESCRIPTION

[0082] In order to further understand the present invention, the asymmetric hydrogenation application provided by the present invention is described in detail below with reference to the examples. It should be understood that these examples are only for further illustrating the features of the present invention, and are not intended to limit the scope of the present invention or the scope of the claims.

[0083] Example 1:

[0084] The racemic substrate rac-1b (2.38 g, 10.0 mmol), catalyst (S)-4e (10.0 mg, 0.01 mmol), KOtBu (1.21 g, 10.0 mmol), and MeOH (15.0 mL) were added to a 50 mL autoclave. The autoclave was pressurized with hydrogen to 5 atm three times, then to 20 atm. The reaction mixture was stirred at room temperature (25°C–30°C) until no significant pressure drop was observed. TfOH (2.0 mL) was then added and stirred for 1 hour to quench the reaction. After quenching, the mixture was extracted with ethyl acetate three times (50 mL x 3). The combined organic phases were washed with brine, dried over anhydrous MgSO₄, and concentrated under reduced pressure. The concentrate was purified by column chromatography (eluent: ethyl acetate / petroleum ether (V / V = 1:10 to 1:4)) to give (R)-1b (1.02 g, yield 43%, 87% ee) and (S)-3b (1.21 g, yield 50%, 91% ee).

[0085] Example 2:

[0086] The racemic substrate rac-1g (2.54 g, 10.0 mmol), catalyst (S)-4e (10.0 mg, 0.01 mmol), KOtBu (1.21 g, 10.0 mmol), and MeOH (15.0 mL) were added to a 50 mL autoclave for hydrogenation. The autoclave was pressurized to 5 atm with hydrogen three times, then to 20 atm. The reaction mixture was stirred at room temperature (25°C–30°C) until no significant pressure drop was observed. The reaction mixture was then quenched by the addition of 1N HCl (20.0 mL) and stirred for 1 hour. After quenching, the mixture was extracted three times with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine, dried over anhydrous MgSO₄, and concentrated under reduced pressure. The concentrate was purified by column chromatography (eluent: ethyl acetate / petroleum ether (V / V = 1:10 to 1:4)) to give (R)-2g (1.43 g, yield 50%, 88% ee) and (S)-3g (1.23 g, yield 48%, 91% ee).

[0087] Example 3:

[0088] The racemic substrate rac-13h (1.20 g, 5.5 mmol), catalyst (R)-4e (5.5 mg, 0.005 mmol), KOtBu (0.67 g, 5.5 mmol), and MeOH (10.0 mL) were added to a 50 mL autoclave. The autoclave was pressurized with hydrogen to 5 atm three times, then to 20 atm. The reaction mixture was stirred at room temperature (25°C-30°C) until no significant pressure drop was observed. The reaction mixture was then quenched by the addition of 1N HCl (20.0 mL) and stirred for 1 hour. After quenching, the mixture was extracted with ethyl acetate three times (50 mL x 3). The combined organic phases were washed with brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The concentrate was purified by column chromatography (eluent: ethyl acetate / petroleum ether (v / v = 1:10)) to afford (R)-14h (0.61 g, 50% yield, 91% ee) and (S)-15 (0.65 g, 47% yield, 94% ee). (S)-15 (0.50 g, 2.0 mmol) and pyridine (3.2 mL, 4.0 mmol) were dissolved in CH2Cl2 (50.0 mL). The mixture was cooled to 0°C in an ice-water bath under nitrogen. Tf2O (0.40 mL, 2.4 mmol) was added at 0°C and stirred for 12 hours at 0°C. After completion of the reaction, the solvent was removed by concentration under reduced pressure. To the concentrate were added Et3N (0.72 mL, 2.0 mol), PPh3 (0.62 g, 0.24 mmol), Pd(OAc)2 (4.4 mg, 2.0 mmol), and DMF (50.0 mL). The reaction system was then heated to 70°C in an oil bath and stirred for 6 hours. After completion, the reaction was quenched with 1N HCl (2.0 mL) and extracted three times with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. The concentrate was purified by column chromatography (eluent: ethyl acetate / petroleum ether (v / v = 1:10)) to afford 408 mg of (S)-16 as a colorless oil in an 87% yield. 1 H NMR(400MHz, CDCl3)δ:7.12-7.02(m,2H),6.95-6.89(m,3H),3.88(s,3H),3.85(s,3H),2.93-2.80(m,1H),2.82-2.70(m,1H) ,2.38(dt,J=9.0,6.2Hz,1H),0.93-0.83(m,1H),0.68-0.51(m,1H),0.31(dq,J=9.5,4.8Hz,1H),0.19(dq,J=9.5,4.8Hz,1H). 13C NMR (100MHz, CDCl3) δ: 174.8, 147.6, 140.7, 127.1, 124.4, 119.1, 111.3, 56.1, 39.5, 35.5, 15.1, 4.3, 2.9.

[0089] Example 4:

[0090] The racemic substrate rac-11p (1.10 g, 5.0 mmol), catalyst (S)-4e (5.0 mg, 0.01 mmol), KOtBu (0.61 g, 5.0 mmol), and MeOH (10.0 mL) were added to a 50 mL autoclave. The autoclave was pressurized with hydrogen to 5 atm three times, then to 20 atm. The reaction mixture was stirred at room temperature (25°C-30°C) until no significant pressure drop was observed. 1N HCl (20.0 mL) was then added and stirred for 1 hour to quench the reaction mixture. After quenching, the mixture was extracted with ethyl acetate three times (50 mL x 3). The combined organic phases were washed with brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The concentrate was purified by column chromatography (eluent: ethyl acetate / petroleum ether (v / v = 1:10)) to afford (S)-12p (0.55 g, 50% yield, 90% ee) and (R)-17 (0.81 g, 47% yield, 94% ee). Following the procedures for the synthesis of (S)-16 and (S)-18, (R)-17 (248 mg, 1.0 mmol) was synthesized as a colorless oil (209 mg, 92% yield). 1 H NMR(400MHz, CDCl3)δ:7.49-7.45(m,2H),7.30-7.24(m,2H),3.65(s,3H),3.60(s,3H),4.03-3 .98(m,1H),2.98(dd,J=15.8,5.2Hz,1H),2.82(dd,J=15.8,10.0Hz,1H),1.86(d,J=2.4Hz,3H). 13 C NMR (100MHz, CDCl3) δ: 157.3, 150.9, 129.1, 127.4, 124.8, 123.5, 117.1, 81.4, 75.9, 60.8, 56.1, 36.0, 27.6, 3.7.

[0091] Example 5:

[0092] Under nitrogen, (R)-2e (314 mg, 1.0 mmol) was dissolved in toluene (10.0 mL). The mixture was cooled to -40°C in a liquid nitrogen-acetone bath, and a solution of DIBAL-H in THF (2.5 mL, 4.0 mmol, 1.6 M) was added with stirring. After the addition, the mixture was stirred at -40°C to -20°C for 9 hours. After the reaction, the mixture was quenched with water (2.0 mL). The quenched solution was extracted with ethyl acetate three times (10 mL x 3). The combined organic phases were washed with brine (10 mL). The organic phase was dried over anhydrous MgSO₄ and concentrated under reduced pressure to afford (R)-19 as a colorless oil (243 mg, 95% yield). 1 H NMR(400MHz, CDCl3)δ:7.77(d,J=7.6Hz,0.51H),7.37-7.27(m,4H),7.22-7.14(m,3H),6.93-6.70(m,2.4 9H),5.67(t,J=3.0Hz,0.84H),5.54(d,J=8.1Hz,0.22H)4.55(dd,J=9.4,6.4Hz,0.47H),4.46(s,2H),4.3 2(dd,J=11.2,5.8Hz,0.85H),4.22(dd,J=11.2,5.9Hz,0.25H),3.83(s,1H),3.75(dt,J=10.6,5.3Hz,0.3 5H),3.57-3.51(m,0.41H),3.29(s,1H),2.51-2.33(m,0.72H),2.31-2.20(m,1H),2.21-2.10(m,1.29H). 13 C NMR (101MHz, CDCl3) δ167.6,158.7,153.1,151.7,144.3,143.7,143.6,133.2,131.0,130.5,129.6,128.9,128.8,128.8,128.6,128.5,128.3, 127.5,127.3,127.1,126.9,126.5,125.4,125.3,122.2,117.2,115.9, 94.5,91.4,65.0,64.9,60.6,52.1,41.6,38.9,38.7,37.1,37.0,36.3.

[0093] Example 6:

[0094] A solution of (R)-19 (0.95 mmol) in MeOH (3.0 mL), (iPr)2NH (0.42 mL, 3.0 mmol), and 10% Pd / C (10 mg, 5% Pd / C, 50% moisture content) were added to a stainless steel autoclave. The autoclave was pressurized to 5 atm with hydrogen three times, then to 20 atm. The reaction mixture was stirred at room temperature (25°C-30°C) until no significant pressure drop was observed. 1N HCl (20.0 mL) was then added and stirred for 1 hour to quench the reaction. After quenching, the reaction mixture was extracted three times with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The concentrate was purified by column chromatography (eluent: petroleum ether / ethyl acetate (v / v = 4:1-2:1)) to afford (R)-20 as a yellow solid, 106-107°C, 301 mg, in a 92% yield. 1 H NMR (400MHz, CDCl3) δ: 7.32 (d, J = 4.3Hz 4H),7.25-7.20(m,1H),7.06(dd,J=8.2,2.3Hz,1H),6.89(d,J=8.2Hz,1H),6.76(s,1H),4.50(dd,J=10.9,4.0 Hz,1H),4.44(s,2H),3.30-3.34(m,2H),2.77-2.73(m,1H),2.46-2.39(m,2H),1.13(dd,J=19.4,6.7Hz,12H).

[0095] Example 7:

[0096] (R)-20 (301 mg, 0.88 mmol) and Et3N (0.12 mL, 1.0 mmol) were dissolved in CH2Cl2 (5 mL). The reaction mixture was cooled to 0°C and iPrCOCl (106 mg, 1.0 mmol) was added dropwise. After the addition was complete, the mixture was heated to 50°C and stirred for 1 hour. After the reaction, the concentrate was concentrated under reduced pressure and purified by column chromatography (eluent: petroleum ether / ethyl acetate (v / v = 4:1 to 2:1)) to obtain 289 mg of (R)-fesoterodine as a colorless oil in an 80% yield. 1H NMR(400MHz, DMSO-d6)δ:7.44-7.38(m,1H),7.31-7.12(m,6H),7.02-6.90(m,1H),5.20(t,J= 5.7Hz,0.73H),4.94-4.89(t,J=5.7Hz,0.27H),4.46(d,J=5.7Hz,1H),4.44-4.28(m,1H),4.1 2(q,J=7.3Hz,1H),2.97-2.83(m,3H),2.31-2.25(m,2H),2.10-2.03(m,1H),2.00(dd,J=13.9 ,7.0Hz,1H),1.26(dd,J=13.2,7.0Hz,4H),1.08(dd,J=13.2,7.0Hz,2H),0.91-0.81(m,12H). 13 C NMR(100MHz, CDCl3)δ:175.5,148.1,143.9,138.9,136.8,128.7,128.5,128.5,128.0,127.1,12 6.3,125.8,122.7,65.1,49.3,48.3,44.1,42.0,36.5,34.4,20.7,20.5,20.0,19.6,19.3,19.1.

[0097] Example 8:

[0098] Under nitrogen, (S)-2q (344 mg, 1.0 mmol), piperonal (155 mg, 1.05 mmol), and (iPr)2NEt (0.21 mL, 1.2 mmol) were added to DCM (4.5 mL). The mixture was stirred at room temperature for 1 hour, then cooled to -25°C in a liquid nitrogen-acetone bath. TiCl4 (0.13 mL, 1.0 mmol) was added dropwise while maintaining the temperature at -25°C. After the addition, the mixture was stirred at -25°C for 15 minutes. After the reaction, the mixture was quenched with water (8 mL). The quenched solution was extracted with DCM (5 mL), and the organic phase was washed with 2 mL of water and concentrated under reduced pressure. The concentrate was purified by column chromatography (eluent: petroleum ether / ethyl acetate (v / v = 10:1)) to afford diastereomer 21 (3:1 ratio) as a white solid, 460 mg, 99% yield. 1H NMR(400MHz, CDCl3)δ:7.23-7.03(m,2H),6.88-6.83(m,J=11.0,5.7,2.5Hz,2H),6.81-6.64(m,3H),6.63-6 .54(m,2H),6.53-6.42(m,1H),6.00-5.96(m,2H),5.30(s,1H),4.73(dd,J=7.6,4.7Hz,0.66H),4.57(dd,J= 8.5,4.4Hz,0.33H),4.45(d,J=3.9Hz,0.66H),3.87-3.81(m,2H),3.77-3.71(m,3H),3.34(dd,J=7.6,3.9Hz ,0.66H),3.28(dd,J=8.5,3.5Hz,0.33H),2.51(dd,J=7.7,4.7Hz,1H),1.83-1.71(m,2H),1.03-1.00(m,3H).

[0099] Example 9:

[0100] 21 (462 mg, 1.0 mmol) was dissolved in CH2Cl2 (5 mL), and CF3CO2H (114 mg, 1.0 mmol) was added dropwise at room temperature. After the addition was complete, the system was heated to 40°C and stirred for 5 hours. After the reaction, the concentrate was concentrated under reduced pressure and purified by column chromatography (eluent: petroleum ether / ethyl acetate (v / v = 10:1)) to obtain 22 as a colorless oil (409 mg, 92% yield). 1 H NMR (400MHz, CDCl3) δ: 7.40 (s, 1H), 7.31 (s, 1H), 7.07 (d, J = 8.8Hz, 1H), 6.95-6.88 (m, 2H), 6.85-6.74 (m, 4H), 5.94-5.87 (m, 2H), 4.4 2(t,J=11.4Hz,2H),3.99(t,J=6.8Hz,2H),3.86(s,3H),2.99(dd,J=14.4,10.9Hz,2H),1.86(q,J=7.0Hz,2H),1.08(t,J=7.4Hz,3H). 13 CNMR(100MHz, CDCl3)δ:169.5,159.2,156.2,148.0,146.8,146.4,140.1,138.1,135.2,129.7,126.8,1 22.5,118.0,113.6,111.7,111.7,110.4,109.0,108.5,101.1,70.1,56.6,56.0,48.3,43.6,22.8,10.7.

[0101] Example 10:

[0102] 22 (250 mg, 0.5 mmol), LiOH (13.0 mg, 0.5 mmol), and K2CO3 (77 mg, 0.5 mmol) were dissolved in toluene (10 mL). Ethylene carbonate (15.0 mg, 1.5 mmol) was added to the mixture at room temperature. After the addition, the mixture was heated to 110°C and stirred for 12 hours. After the reaction, the mixture was concentrated under reduced pressure and purified by column chromatography (eluent: petroleum ether / ethyl acetate (v / v = 4:1)) to obtain the diastereomers of enlasentan (4:1) as a white solid, 180 mg, in an 82% yield. 1 HNMR (400MHz, CDCl3) δ: 6.87 (d, J = 8.6Hz, 1H), 6.81-6.75 (m, 3H), 6.75-6.70 (m, 2H), 6.69-6.64 ( m,1H),6.54(d,J=2.2Hz,1H),5.95-5.93(m,1.72H),5.89-5.88(m,0.28H),5.35(t,J=4.8Hz,0.1 4H), 4.95 (d, J=9.6Hz, 0.86H), 4.71 (d, J=7.7Hz, 0.14H), 4.50 (d, J=9.6Hz, 0.86H), 3.81 (t, J=6. 6Hz, 2H), 3.76–3.36 (m, 7H), 3.33 (t, J = 9.6Hz, 1H), 1.75 (q, J = 7.0Hz, 2H), 0.99 (t, J = 7.4Hz, 3H).

[0103] Example 11:

[0104] (S)-2p (316 mg, 1.0 mmol), KOH (56 mg, 1.0 mmol), and MeOH (4.5 mL) were mixed and stirred at room temperature for 10 h. After stirring, MeI (282 mg, 2.0 mmol) was added dropwise at room temperature and stirring continued for 6 h. After completion of the reaction, the reaction solution was quenched with 1N HCl (2 mL) and extracted three times with ethyl acetate (5 mL x 3). The organic layers were combined and washed with 2 mL of water, and the resulting organic phase was concentrated under reduced pressure. The resulting concentrate was dissolved in DMF (5.0 mL), and MsOH (96 mg, 1.0 mmol) was added at room temperature. The reaction system was heated to 70°C in an oil bath and stirred for 3 h. After completion of the reaction, the reaction solution was quenched with H2O (5 mL) and extracted with ethyl acetate (5 mL). The organic phases were combined and washed with 2 mL of water, and the resulting organic phase was concentrated under reduced pressure. The concentrate was purified by column chromatography (eluent: petroleum ether / ethyl acetate (v / v = 10:1)) to give (S)-24 as a white solid, mp 134-135 ° C, yield 66%. 1 H NMR (400MHz, CDCl3) δ: 6.97 (d, J = 8.5Hz, 2H), 6.84 (d, J = 2.1Hz, 1H), 6.78 (d, J = 8.6Hz, 2H), 6.63 (d, J = 2.1Hz, 1H), 4.53 (d d,J=8.1,1.7Hz,1H),3.86(s,3H),3.77(s,3H),3.66(s,3H),3.19(dd,J=19.3,7.9Hz,1H),2.58(dd,J=19.2,2.2Hz,1H). 13 C NMR (100MHz, CDCl3) δ: 206.7, 161.8, 158.2, 158.0, 139.9, 139.1, 136.2, 128.1, 113.9, 106.3, 100.1, 95.9, 55.9, 55.7, 55.4, 47.9, 40.6.

[0105] Example 12:

[0106] Aryl and substituted aryl substrate structures (1b to 1r) and reaction equations:

[0107]

[0108] The racemic substrate rac-1b (1.0 mmol), catalyst (R)-4e (1.0 mg, 0.001 mmol), t-BuOK (0.12 g, 1.0 mmol), and MeOH (2.0 mL) were added to a 20 mL autoclave. The autoclave was pressurized to 5 atm with hydrogen three times and then to 10 atm. The reaction mixture was stirred at room temperature (25°C–30°C) until no significant pressure drop was observed. The reaction mixture was then quenched with 1N HCl (2 mL) and extracted three times with ethyl acetate (5 mL x 3). The combined organic phases were washed with brine, dried over anhydrous MgSO₄, and concentrated under reduced pressure. The concentrate was purified by column chromatography (eluent: ethyl acetate / petroleum ether (v / v = 1:10–1:4)) to afford (S)-2b (yield 43%, 87.4% ee) and (R)-3b (yield 49%, 91.1% ee). Characterization data of (S)-2b: Colorless oil, 114 mg, 43% yield, 87.4% ee. 1 H NMR(400MHz, CDCl3)δ:7.26(d,J=3.8Hz,4H),7.23-7.12(m,1H),6.87-6.80(m,2H),6.67(d,J=7 .8Hz,1H),6.20(s,1H),4.85(t,J=7.8Hz,1H),3.59(s,3H),3.11(d,J=7.8Hz,2H),2.18(s,3H). 13 C NMR (100MHz, CDCl3) δ: 173.9, 151.2, 143.0, 130.0, 129.7, 128.7, 128.4, 128.1, 127.8, 126.4, 116.4, 51.9, 40.0, 39.5, 20.6. (c 1.0, MeOH). HPLC conditions: chiral column (25 cm × 0.46 cm ID); n-hexane / 2-propanol = 85:15; temperature, room temperature, flow rate = 1.0 mL / min; 210 nm UV detector; t R (R) = 15.77 min; t R (S)=18.25min.HRMS(ESI)Calcd for C 17 H 19 O3([M+H] + ):271.1329,Found:271.1324. Characterization data of (R)-3b: white solid, mp 118-120 ° C, 119 mg, 49% yield, 91.1% ee. 1HNMR(400MHz, CDCl3)δ:7.34-7.26(m,4H),7.23-7.17(m,1H),6.87-6.80(m,1H),6.78-6.64(m,3H),4.59-4.55 (m,1H),3.87-3.67(m,1H),3.62-3.33(m,1H),2.78(s,1H),2.39-2.31(m,1H),2.16(s,3H),2.15-2.03(m,1H). 13 C NMR (100MHz, CDCl3) δ: 151.6, 144.2, 130.6, 130.3, 129.3, 128.6, 128.4, 128.0, 126.4, 116.1, 60.8, 38.8, 37.1, 20.8. (c 1.0,MeOH)[lit. 13 (c 1.0, MeOH)]. HPLC conditions: chiral column (25 cm × 0.46 cm ID); n-hexane / 2-propanol = 90:10; temperature, room temperature, flow rate = 1.0 mL / min; 220 nm UV detector; t R (R) = 10.87 min; t R (S)=17.88min.HRMS(ESI)Calcd for C 16 H 19 O2([M+H] + ):243.1380,Found:243.1374.

[0109] Example 13:

[0110] The racemic substrate rac-1c (1.0 mmol), catalyst (R)-4e (1.0 mg, 0.001 mmol), t-BuOK (0.12 g, 1.0 mmol), and MeOH (2.0 mL) were added to a 20 mL autoclave. The autoclave was pressurized with hydrogen to 5 atm three times and then to 10 atm. The reaction mixture was stirred at room temperature (25°C–30°C) until no significant pressure drop was observed. The reaction mixture was then quenched with 1N HCl (2 mL) and extracted three times with ethyl acetate (5 mL x 3). The combined organic phases were washed with brine, dried over anhydrous MgSO₄, and concentrated under reduced pressure. The concentrate was purified by column chromatography (eluent: ethyl acetate / petroleum ether (v / v = 1:10–1:4)) to afford (S)-2c (yield 45%, 89.1% ee) and (R)-3c (yield 48%, 85.3% ee). Characterization data of (S)-2c: colorless oil, 129 mg, 45% yield, 89.1% ee. 1 H NMR (400MHz, CDCl3) δ: 7.25 (m, 4H), 7.17 (t, J = 6.6Hz, 1H), 6.73 (d, J = 8.4Hz, 1H), 6.66-6.45 (m,1H),5.93(s,1H),4.82(t,J=7.8Hz,1H),3.65(s,3H),3.60(s,3H),3.09(d,J=7.7Hz,2H). 13 C NMR (100MHz, CDCl3) δ: 153.9, 147.8, 143.9, 132.3, 128.5, 128.3, 126.4, 116.8, 114.9, 111.9, 60.7, 55.7, 39.0, 37.1. (c 1.0, MeOH). HPLC conditions: chiral column (25 cm × 0.46 cm ID); n-hexane / 2-propanol = 90:10; temperature, room temperature, flow rate = 1.0 mL / min; 220 nm UV detector; t R (R) = 8.67 min; t R (S)=10.02min.HRMS(ESI)Calcd for C 16 H 19 O2([M+H] + ):287.1278,Found:287.1271. Characterization data of (R)-3c: white solid, mp 104-105 ° C. 124 mg, 48% yield, 85.3% ee. 1HNMR (400MHz, CDCl3) δ: 7.30 (d, J = 4.1Hz, 4H), 7.24-7.18 (dt, J = 8.6, 4.0Hz, 1H), 6.78 (d, J = 8.7Hz, 1H), 6.63 (dd, J = 8.7, 3.0Hz, 1H), 6.56 (d, J = 2.9Hz, 1H),5.90(s,1H),4.56(dd,J=10.0,5.9Hz,1H),3.78-3.36(m,1H),3.67(s, 3H),3.56-3.49(m,1H),2.40-2.32(m,1H),2.20-2.12(m,1H),1.99(s,1H). 13 C NMR (100MHz, CDCl3) δ: 153.9, 147.8, 143.9, 132.3, 128.5, 128.3, 126.4, 116.8, 114.9, 111.9, 60.7, 55.7, 39.0, 37.1. (c 1.0, MeOH). HPLC conditions: chiral column (25 cm × 0.46 cm ID); n-hexane / 2-propanol = 90:10; temperature, room temperature, flow rate = 1.0 mL / min; 220 nm UV detector; t R (S) = 10.36 min; t R (R)=12.84min.HRMS(ESI)Calcd for C 16 H 19 O3([M+H] + ):259.1329,Found:259.1321.

[0111] Example 14:

[0112] The racemic substrate rac-1d (1.0 mmol), catalyst (R)-4e (1.0 mg, 0.001 mmol), t-BuOK (0.12 g, 1.0 mmol), and MeOH (2.0 mL) were added to a 20 mL autoclave. The autoclave was pressurized with hydrogen to 5 atm three times and then to 10 atm. The reaction mixture was stirred at room temperature (25°C–30°C) until no significant pressure drop was observed. The reaction mixture was then quenched with 1N HCl (2 mL) and extracted three times with ethyl acetate (5 mL x 3). The combined organic phases were washed with brine, dried over anhydrous MgSO₄, and concentrated under reduced pressure. The concentrate was purified by column chromatography (eluent: ethyl acetate / petroleum ether (v / v = 1:10–1:4)) to afford (S)-2d (yield 47%, 83.7% ee) and (R)-3d (yield 47%, 87.1% ee). Characterization data of (S)-2d: colorless oil, 137 mg, 47% yield, 83.7% ee. 1 H NMR(400MHz, CDCl3)δ:7.39-7.27(m,3H),7.27-7.18(m,3H),7.07-6.91(m,2H),6.74(dd, J=8.5,5.0Hz,1H),6.58(s,1H),4.84(t,J=7.8Hz,1H),3.64(s,3H),3.11(d,J=8.0Hz,2H). 13 C NMR (100MHz, CDCl3) δ: 174.0, 152.2, 142.1, 132.4, 128.7, 128.2, 127.8, 127.7, 126.9, 125.7, 118.3, 52.3, 39.6, 39.5. (c 1.0, MeOH). HPLC conditions: chiral column (25 cm × 0.46 cm ID); nhexane / 2-propanol = 94:6; temperature, room temperature, flow rate = 1.0 mL / min; 220 nm UV detector; t R (S) = 16.59 min; t R (R)=19.31min.HRMS(ESI)Calcd for C 16 H 16 ClO3([M+H] + ):291.0782,Found:291.0771. Characterization data of (R)-3d: white solid, mp 122-123 ° C. 121 mg, 46% yield, 87.1% ee. 1H NMR(400MHz, CDCl3)δ:7.40-7.17(m,4H),7.03(dd,J=8.6,2.6Hz,1H),6.92(d,J=2.6Hz,1H),6.78(d,J=8.6Hz,1H), 4.55(dd,J=9.8,6.0Hz,1H),3.80(dt,J=10.3,5.0Hz,1H),3.57-3.50(m,1H),2.42-2.33(m,1H),2.19-2.11(m,1H). 13 C NMR (100MHz, CDCl3) δ: 152.7, 143.1, 132.8, 128.8, 128.6, 128.3, 127.5, 126.9, 126.0, 118.0, 60.7, 38.9, 36.8. (c 1, MeOH). HPLC conditions: chiral column (25 cm × 0.46 cm ID); n-hexane / 2-propanol = 90:10; temperature, room temperature, flow rate = 1.0 mL / min; 220 nm UV detector; t R (S) = 9.00 min; t R (R)=9.66min.HRMS(ESI)Calcdfor C 15 H 15 ClNaO2([M+Na] + ):285.0653,Found:285.0651.

[0113] Example 15:

[0114] The racemic substrate rac-1e (1.0 mmol), catalyst (R)-4e (1.0 mg, 0.001 mmol), t-BuOK (0.12 g, 1.0 mmol), and MeOH (2.0 mL) were added to a 20 mL autoclave. The autoclave was pressurized with hydrogen to 5 atm three times and then to 10 atm. The reaction mixture was stirred at room temperature (25°C–30°C) until no significant pressure drop was observed. The reaction mixture was then quenched with 1N HCl (2 mL) and extracted three times with ethyl acetate (5 mL x 3). The combined organic phases were washed with brine, dried over anhydrous MgSO₄, and concentrated under reduced pressure. The concentrate was purified by column chromatography (eluent: ethyl acetate / petroleum ether (v / v = 1:10–1:4)) to afford (S)-2e (yield 47%, 83.7% ee) and (R)-3e (yield 47%, 87.1% ee). Characterization data of (S)-2e: white solid, mp 125-126°C. 154 mg, 49% yield, 93.7% ee. 1H NMR(400MHz, CDCl3)δ:7.81-7.78(m,2H),7.32-7.28(m,2H),7.24-7.20(m,1H),6.84(dd,J=8.2,1. 6Hz,1H),6.69(d,J=8.5Hz,1H),4.85(t,J=7.7Hz,1H),3.84(s,1H),3.65(s,2H),3.22-3.13(m,2H). 13 C NMR (100MHz, CDCl3) δ: 173.9, 167.3, 158.2, 142.4, 130.4, 130.2, 130.0, 128.8, 127.9, 126.9, 122.6, 116.6, 52.3, 52.1, 39.8, 39.6. (c 1, MeOH). HPLC conditions: chiral column (25 cm × 0.46 cm ID); n-hexane / 2-propanol = 90:10; temperature, room temperature, flow rate = 1.0 mL / min; 210 nm UV detector; t R (S) = 9.09 min; t R (R)=10.66min.HRMS(ESI)Calcd for C 18 H 19 O5([M+H] + ):315.1227, Found:315.1221. Characterization data of (R)-3e: white solid, mp 120-121 ° C. 143 mg, 50% yield, 84.7% ee. 1 H NMR (400MHz, CDCl3) δ: 8.16 (s, 1H), 7.78 (d, J = 2.2Hz, 1H), 7.71 (dd, J = 8.4, 2.2Hz, 1H), 7.25-7.20 (m, 4H), 7.17-7.13 (m, 1H), 6.79 (d, J =8.5Hz,1H),4.58(t,J=7.8,1H),3.80(s,3H),3.68-3.63(m,1H),3.56-3.50(m,1H),2.91(s,1H),2.38-2.28(m,1H),2.24-2.16(m,1H). 13 C NMR (100MHz, CDCl3) δ:167.8,158.8,143.4,131.1,130.5,129.7,128.6,128.3,126.6,122.2,115.9,60.8,52.1,39.0,37.1., (c 1.0, MeOH). HPLC conditions: chiral column (25 cm × 0.46 cm ID); n-hexane / 2-propanol = 90:10; temperature, room temperature, flow rate = 1.0 mL / min; 210 nm UV detector; t R (S) = 8.15 min; t R (R)=9.89min.HRMS(ESI)Calcdfor C 17 H 19 O4([M+H] + ):287.1278,Found:287.1269.

[0115] Example 16:

[0116] The racemic substrate rac-1f (1.0 mmol), catalyst (R)-4e (1.0 mg, 0.001 mmol), t-BuOK (0.12 g, 1.0 mmol), and MeOH (2.0 mL) were added to a 20 mL autoclave. The autoclave was pressurized with hydrogen to 5 atm three times and then to 10 atm. The reaction mixture was stirred at room temperature (25°C–30°C) until no significant pressure drop was observed. The reaction mixture was then quenched with 1N HCl (2 mL) and extracted three times with ethyl acetate (5 mL x 3). The combined organic phases were washed with brine, dried over anhydrous MgSO₄, and concentrated under reduced pressure. The concentrate was purified by column chromatography (eluent: ethyl acetate / petroleum ether (v / v = 1:10–1:4)) to afford (S)-2f (yield 47%, 91.2% ee) and (R)-3f (yield 50%, 88.0% ee). Characterization data of (S)-2f: colorless oil, 127 mg, 47% yield; 91.2% ee. 1 H NMR(400MHz, CDCl3)δ:7.34-7.22(m,4H),7.22-7.12(m,1H),6.91(d,J=7.8Hz,1H),6.66(d,J=8.0Hz,1H),6 .62(s,1H),6.12(d,J=14.6Hz,1H),4.82(t,J=7.6Hz,1H),3.61(s,3H),3.11(d,J=7.6Hz,2H),2.22(s,3H). 13 C NMR (100MHz, CDCl3) δ: 174.1, 153.3, 143.2, 137.8, 128.6, 128.1, 127.9, 127.5, 126.6, 121.7, 117.5, 52.1, 39.7, 21.0. (c 1.0, CHCl3). HPLC conditions: chiral column (25 cm × 0.46 cm ID); n-hexane / 2-propanol = 85:15; temperature, room temperature, flow rate = 1.0 mL / min; 210 nm UV detector; t R (R) = 10.07 min; t R (S)=11.45min.HRMS(ESI)Calcd for C 17 H 19 O3([M+H] + ):271.1329, Found:271.1324(R)-3f characterization data: white solid, mp 87-88 ° C, 121 mg, 50% yield, 88.0% ee. 1 H NMR(400MHz, CDCl3)δ:7.46-7.56(m,1H),7.28-7.20(m,4H),7.16-7.13(m,1H),6.82(d,J=7.8Hz,1H),6.65-6.40( m,2H),4.58-4.52(m,1H),3.70-3.61(m,1H),3.54-3.44(m,2H),2.39-2.25(m,1H),2.16(s,3H),2.13-2.00(m,1H). 13 C NMR (100MHz, CDCl3) δ: 152.3, 144.1, 130.4, 129.0, 128.6, 128.3, 126.5, 126.4, 124.8, 120.7, 60.8, 39.3, 37.1, 16.4. (c 1.0, CHCl3). HPLC conditions: chiral column (25 cm × 0.46 cm ID); nhexane / 2-propanol = 85:15; temperature, room temperature, flow rate = 1.0 mL / min; 220 nm UV detector; t R (R) = 18.96 min; t R (S)=26.18min.HRMS(ESI)Calcd for C 16 H 19 O2([M+H] + ):243.1380,Found:243.1373.

[0117] Example 17:

[0118] The racemic substrate rac-1g (1.0 mmol), catalyst (R)-4e (1.0 mg, 0.001 mmol), t-BuOK (0.12 g, 1.0 mmol), and MeOH (2.0 mL) were added to a 20 mL autoclave. The autoclave was pressurized with hydrogen to 5 atm three times and then to 10 atm. The reaction mixture was stirred at room temperature (25°C–30°C) until no significant pressure drop was observed. The reaction mixture was then quenched with 1N HCl (2 mL) and extracted three times with ethyl acetate (5 mL x 3). The combined organic phases were washed with brine, dried over anhydrous MgSO₄, and concentrated under reduced pressure. The concentrate was purified by column chromatography (eluent: ethyl acetate / petroleum ether (v / v = 1:10–1:4)) to afford the products (S)-2g (yield 51%, 86.8% ee) and (R)-3g (yield 48%, 89.1% ee). Characterization data of (S)-2g: colorless oil, 137 mg, 51% yield, 86.8% ee. 1 H NMR(400MHz, CDCl3)δ:7.32-7.27(m,2H),7.26-7.16(m,3H),6.90(d,J=9.2Hz,1H),6.43-6.40( m,2H),6.26(s,1H),4.76(dd,J=8.8,6.5Hz,1H),3.73(s,3H),3.65(s,3H),3.11(d,J=7.6,2H). 13 C NMR (100MHz, CDCl3) δ: 159.1, 154.9, 144.4, 129.4, 128.7, 128.6, 128.3, 126.4, 123.2, 106.8, 102.4, 60.9, 55.4, 38.5, 37.1. (c 1.0, CHCl3). HPLC conditions: chiral column (25 cm × 0.46 cm ID); n-hexane / 2-propanol = 90:10; temperature, room temperature, flow rate = 1.0 mL / min; 210 nm UV detector; t R (R) = 4.00 min; t R (S)=4.63min.HRMS(ESI)Calcd for C 17 H 19 O4([M+H] + ):287.3345,Found:287.3340. Characterization data of (R)-3g: white solid, mp 89-90 ° C, 124 mg, 48% yield, 89.1% ee. 1H NMR(400MHz, CDCl3)δ:7.34-7.27(m,4H),7.23-7.19(m,1H),6.86(d,J=8.3Hz,1H),6.47-6.36(m,2H),6.23(s,1H),4.47(dd,J=1 0.1,5.7Hz,1H),3.80(dt,J=10.0,4.8Hz,1H),3.74(s,3H),3.60-3.53(m,1H),2.41-2.33(m,1H),2.19-2.12(m,1H),1.77(s,1H). 13 C NMR (100MHz,CDCl3)δ: 1 157.9,153.7,136.1,131.2,129.2,128.7,127.3,121.0,116.0,113.8,60.7,55.3,37.9,37.3. (c 1.0, CHCl3). HPLC conditions: chiral column (25 cm × 0.46 cm ID); n-hexane / 2-propanol = 90:10; temperature, room temperature, flow rate = 1.0 mL / min; 210 nm UV detector; t R (R) = 4.63 min; t R (S)=6.22min.HRMS(ESI)Calcd for C 16 H 19 O3([M+H] + ):259.3245,Found:259.3241.

[0119] Example 18:

[0120] The racemic substrate rac-1h (1.0 mmol), catalyst (R)-4e (1.0 mg, 0.001 mmol), t-BuOK (0.12 g, 1.0 mmol), and MeOH (2.0 mL) were added to a 20 mL autoclave. The autoclave was pressurized with hydrogen to 5 atm three times and then to 10 atm. The reaction mixture was stirred at room temperature (25°C–30°C) until no significant pressure drop was observed. The reaction mixture was then quenched with 1N HCl (2 mL) and extracted three times with ethyl acetate (5 mL x 3). The combined organic phases were washed with brine, dried over anhydrous MgSO₄, and concentrated under reduced pressure. The concentrate was purified by column chromatography (eluent: ethyl acetate / petroleum ether (v / v = 1:10–1:4)) to afford (S)-2h (yield 45%, 88.2% ee) and (R)-3h (yield 47%, 90.6% ee). Characterization data of (S)-2h: colorless oil, 121 mg, 45% yield, 88.2% ee. 1 H NMR(400MHz, CDCl3)δ:7.26(d,J=6.5Hz,4H),7.22-7.12(m,1H),6.91(d,J=7.8Hz,1H),6.66(d,J=7.9Hz,1H) ,6.62(s,1H),6.12(d,J=14.8Hz,1H),4.82(t,J=7.8Hz,1H),3.61(s,3H),3.11(d,J=7.6Hz,2H),2.22(s,3H). 13 C NMR (100MHz, CDCl3) δ: 174.1, 153.3, 143.2, 137.8, 128.6, 128.1, 127.9, 127.5, 126.6, 121.7, 117.5, 52.1, 39.7, 21.0. (c 1.0, CHCl3). HPLC conditions: chiral column (25 cm × 0.46 cm ID); n-hexane / 2-propanol = 90:10; temperature, room temperature, flow rate = 1.0 mL / min; 210 nm UV detector; t R (R) = 9.19 min; t R (S)=10.75min.HRMS(ESI)Calcd for C 16 H 19 O3([M+H] + ):271.1329,Found:271.1325. Characterization data of (R)-3h: white solid, mp 67-68 ° C, 114 mg, 47% yield, 90.6% ee. 1H NMR(400MHz, CDCl3)δ:7.31-7.29(m,4H),7.23-7.16(m,1H),6.98(d,J=7.2Hz,1H),6.86(d,J=7.5Hz,1H),6.76(t,J=7.5Hz,1H),6.01(s,1H),4 .56(dd,J=9.6,6.1Hz,1H),3.78(dt,J=10.4,5.1Hz,1H),3.55(td,J=10 .3,9.8,4.5Hz,1H),2.41-2.35(m,1H),2.25(s,3H),2.32-2.15(m,1H). 13 C NMR(100MHz, CDCl3)δ:152.3,144.1,130.4,129.0,128.6,128.3,126.5,126.4,124.8,120.7,60.8,39.3,37.1,16.4., (c1.0, CHCl3). HPLC conditions: chiral column (25 cm × 0.46 cm ID); n-hexane / 2-propanol = 90:10; temperature, room temperature, flow rate = 1.0 mL / min; 210 nm UV detector; t R (S) = 9.07 min; t R (R)=9.75min.HRMS(ESI)Calcd for C 16 H 19 O2([M+H] + ):243.1380,Found:243.1381.

[0121] Example 19:

[0122] The racemic substrate rac-1i (1.0 mmol), catalyst (R)-4e (1.0 mg, 0.001 mmol), t-BuOK (0.12 g, 1.0 mmol), and MeOH (2.0 mL) were added to a 20 mL autoclave. The autoclave was pressurized with hydrogen to 5 atm three times and then to 10 atm. The reaction mixture was stirred at room temperature (25°C–30°C) until no significant pressure drop was observed. The reaction mixture was then quenched with 1N HCl (2 mL) and extracted three times with ethyl acetate (5 mL x 3). The combined organic phases were washed with brine, dried over anhydrous MgSO₄, and concentrated under reduced pressure. The concentrate was purified by column chromatography (eluent: ethyl acetate / petroleum ether (v / v = 1:10–1:4)) to afford (S)-2i (yield 44%, 98.2% ee) and (R)-3i (yield 50%, 80.7% ee). Characterization data of (S)-2i: Colorless oil, 125 mg, 44% yield, 98.2% ee. 1 H NMR (400MHz, CDCl3) δ: 7.14-7.05 (m, 3H), 7.04-6.98 (m, 1H), 6.88 (d, J = 8.4Hz, 1H), 6.7 8(s,1H),4.28-4.21(m,1H),3.80(s,3H),3.18-2.68(m,2H),2.26(s,3H),1.54(s,3H). 13 C NMR(100MHz, CDCl3)δ:167.8,158.8,149.4,134.1,132.3,129.0,128.4,125.6,116.7,114.3,55.1,39.8,37.2,20.6., (c 1.0, CHCl3). HPLC conditions: chiral column (25 cm × 0.46 cm ID); n-hexane / 2-propanol = 93:7; temperature, room temperature, flow rate = 1.0 mL / min; 210 nm UV detector; t R (R) = 17.19 min; t R (S)=20.15min.HRMS(ESI)Calcd for C 18 H 21 O3([M+H] + ):285.1485,Found:285.1481. Characterization data of (R)-3i: white solid, 128 mg, 50% yield, 80.7% ee. 1H NMR(400MHz, CDCl3)δ:7.24-7.14(m,2H),6.94-6.82(m,3H),6.77(s,1H),6.71(d,J=8.1Hz,1H),4.63- 4.37(m,1H),3.90-3.66(m,4H),3.60-3.46(m,1H),2.42-2.28(m,1H),2.18(s,3H),2.16-1.87(m,1H). 13 C NMR (100MHz, CDCl3) δ: 157.8, 151.3, 135.9, 130.6, 130.0, 129.0, 128.9, 127.6, 115.9, 113.7, 60.6, 55.1, 37.8, 37.0, 20.5. (c 1.0, MeOH). HPLC conditions: chiral column (25 cm × 0.46 cm ID); n-hexane / 2-propanol = 93:7; temperature, room temperature, flow rate = 1.0 mL / min; 210 nm UV detector; t R (S) = 14.82 min; t R (R)=16.12min.HRMS(ESI)Calcd for C 17 H 21 O2([M+H] + ):257.1536,Found:257.1534.

[0123] Example 20:

[0124] The racemic substrate rac-1j (1.0 mmol), catalyst (R)-4e (1.0 mg, 0.001 mmol), t-BuOK (0.12 g, 1.0 mmol), and MeOH (2.0 mL) were added to a 20 mL autoclave. The autoclave was pressurized to 5 atm with hydrogen three times, then to 10 atm. The reaction mixture was stirred at room temperature (25°C–30°C) until no significant pressure drop was observed. The reaction mixture was then quenched with 1N HCl (2 mL) and extracted three times with ethyl acetate (5 mL x 3). The combined organic phases were washed with brine, dried over anhydrous MgSO₄, and concentrated under reduced pressure. The concentrate was purified by column chromatography (eluent: ethyl acetate / petroleum ether (v / v = 1:10–1:4)) to afford (S)-2j (yield 50%, 89.2% ee) and (R)-3j (yield 48%, 99.5% ee). Characterization data of (S)-2j: white solid, mp 80-82 °C, 126 mg, 50% yield, 89.2% ee. 414 mg, 82% yield.1 H NMR(400MHz, CDCl3)δ:7.30-7.25(m,2H),7.24-7.19(m,1H),7.10(d,J=7.6Hz,1H),7.08-7.00(m ,2H),6.90(d,J=7.6Hz,1H),4.39(t,J=4.5Hz,1H),3.09-3.00(m,2H),2.35(s,3H),2.15(s,3H). 13 C NMR (100MHz, CDCl3) δ: 167.5, 150.5, 140.5, 134.2, 130.5, 129.2, 127.5, 127.1, 126.0, 124.2, 123.1, 38.5, 37.7, 18.7, 15.9. (c 1.0, MeOH). HPLC conditions: chiral column (25 cm × 0.46 cm ID); n-hexane / 2-propanol = 93:7; temperature, room temperature, flow rate = 1.0 mL / min; 210 nm UV detector; t R (R) = 11.20 min; t R (S) = 14.67 min. Characterization data of (R)-3j: white solid, mp 130-132 ° C. 123 mg, 48% yield, 99.5% ee. 1 H NMR(400MHz, CDCl3)δ:7.35-7.26(m,4H),7.24-7.16(m,1H),6.92(d,J=7.6Hz,1H),6.66(d,J=7.6Hz,1H),4.82-4 .73(m,1H),3.88-3.67(m,1H),3.56-3.48(m,1H),2.64-2.52(m,1H),2.47-2.28(m,1H),2.18(s,6H),1.63(s,1H). 13 C NMR (100MHz, CDCl3) δ: 153.0, 143.7, 135.9, 129.0, 128.6, 128.5, 127.5, 126.2, 123.4, 123.0, 61.3, 38.1, 33.4, 20.8, 16.2. (c 1.0, CHCl3). HPLC conditions: Chiralcel AS-H column (25 cm × 0.46 cm ID); n-hexane / 2-propanol = 90:10; temperature, room temperature, flow rate = 1.0 mL / min; 220 nm UV detector; t R (S) = 29.22 min; tR (R)=39.38min.HRMS(ESI)Calcdfor C 17 H 21 O2([M+H] + ):257.1536,Found:257.1534.

[0125] Example 21:

[0126] The racemic substrate rac-1k (1.0 mmol), catalyst (R)-4e (1.0 mg, 0.001 mmol), t-BuOK (0.12 g, 1.0 mmol), and MeOH (2.0 mL) were added to a 20 mL autoclave. The autoclave was pressurized to 5 atm with hydrogen three times and then to 10 atm. The reaction mixture was stirred at room temperature (25°C–30°C) until no significant pressure drop was observed. The reaction mixture was then quenched with 1N HCl (2 mL) and extracted three times with ethyl acetate (5 mL x 3). The combined organic phases were washed with brine, dried over anhydrous MgSO₄, and concentrated under reduced pressure. The concentrate was purified by column chromatography (eluent: ethyl acetate / petroleum ether (v / v = 1:10–1:4)) to afford (S)-2k (yield 53%, 83.2% ee) and (R)-3k (yield 45%, 95.7% ee). Characterization data of (S)-2k: Colorless oil, 143 mg, 53% yield, 83.2% ee. 1 H NMR(400MHz, CDCl3)δ:7.14(d,J=7.9Hz,2H),7.12-6.99(m,4H),6.83(t,J=7.4Hz,1H),6.76(d, J=8.1Hz,1H),6.27(s,1H),4.84(t,J=7.6Hz,1H),3.60(s,3H),3.22-3.00(m,1H),2.28(s,3H). 13 C NMR (100MHz, CDCl3) δ: 173.9, 151.2, 143.1, 130.5, 130.4, 129.0, 128.7, 128.4, 127.9, 126.7, 117.1, 52.2, 39.8, 39.7, 20.9. (c 1.0, MeOH). HPLC conditions: Chiralcel OD-3 column (25 cm × 0.46 cm ID); n-hexane / 2-propanol = 90:10; temperature, room temperature, flow rate = 1.0 mL / min; 220 nm UV detector; t R (R) = 5.72 min; t R(S)=7.63min.HRMS(ESI)Calcd for C 17 H 19 O3([M+H] + ):271.1329,Found:271.1324. Characterization data of (R)-3k: white solid, mp 91-92 ° C.109 mg, 45% yield, 95.7% ee. 1 H NMR (400MHz, CDCl3) δ: 7.19 (d, J = 8.0Hz, 2H), 7.12 (d, J = 8.0Hz, 2H), 7.09-7.03 (m, 1H), 7.00 (d, J = 7.6Hz, 1H), 6.83 (dd, J = 13.6, 7.6Hz, 2H), 6. 72(s,1H),4.56(dd,J=9.7,6.1Hz,1H),3.78-3.75(m,1H),3.58-3.52( m,1H),2.54(s,1H),2.41-2.34(m,1H),2.34(s,3H),2.20-2.12(m,1H). 13 C NMR (100MHz, CDCl3) δ: 153.8, 141.0, 135.9, 131.1, 129.2, 128.8, 128.2, 127.4, 121.1, 116.1, 60.8, 38.4, 37.2, 21.1. (c 1.0, MeOH). HPLC conditions: Chiralcel OD-3 column (25 cm × 0.46 cm ID); n-hexane / 2-propanol = 90:10; temperature, room temperature, flow rate = 1.0 mL / min; 220 nm UV detector; t R (S) = 8.96 min; t R (R)=11.75min.HRMS(ESI)Calcd for C 16 H 19 O2([M+H] + ):243.1380,Found:243.1380.

[0127] Example 22:

[0128] The racemic substrate rac-1l (1.0 mmol), catalyst (R)-4e (1.0 mg, 0.001 mmol), t-BuOK (0.12 g, 1.0 mmol), and MeOH (2.0 mL) were added to a 20 mL autoclave. The autoclave was pressurized to 5 atm with hydrogen three times, then to 10 atm. The reaction mixture was stirred at room temperature (25°C–30°C) until no significant pressure drop was observed. The reaction mixture was then quenched with 1N HCl (2 mL) and extracted three times with ethyl acetate (5 mL x 3). The combined organic phases were washed with brine, dried over anhydrous MgSO₄, and concentrated under reduced pressure. The concentrate was purified by column chromatography (eluent: ethyl acetate / petroleum ether (v / v = 1:10–1:4)) to afford (S)-2l (yield 45%, 90.5% ee) and (R)-3l (yield 50%, 84.3% ee). Characterization data of (S)-2l: colorless oil, 129 mg, 45% yield, 90.5% ee. 1 H NMR(400MHz, CDCl3)δ:7.21-7.15(m,2H),7.12-7.02(m,2H),6.90-6.79(m,4H), 6.11(s,1H),4.82(t,J=7.8Hz,1H),3.77(s,3H),3.63(s,3H),3.18-3.03(m,2H). 13 C NMR (100MHz, CDCl3) δ: 173.9, 158.1, 153.5, 135.0, 130.6, 128.9, 128.1, 127.6, 120.7, 116.5, 113.9, 55.2, 52.0, 39.8, 39.4. (c1.0, MeOH). HPLC conditions: Chiralcel OD-3 column (25 cm × 0.46 cm ID); n-hexane / 2-propanol = 90:10; temperature, room temperature, flow rate = 1.0 mL / min; 220 nm UV detector; t R (R) = 8.99 min; t R (S)=9.68min.HRMS(ESI)Calcd for C 17 H 19 O4([M+H] + ):287.1278,Found:287.1278. Characterization data of (R)-3l: white solid, mp 98-99 ° C.129 mg, 50% yield, 84.3% ee. 1H NMR(400MHz, CDCl3)δ:7.20(d,J=8.6Hz,2H),7.07-7.02(m,1H),6.97(d,J=7.5Hz,1H),6.88-6.76(m,5H),4.54(dd, J=9.7,6.1Hz,1H),3.77(s,4H),3.74-3.72(m,1H),3.55-3.50(m,1H),2.64(s,1H),2.38-2.28(m,1H),2.13(m,1H). 13 C NMR (100MHz, CDCl3) δ: 157.9, 153.7, 136.2, 131.3, 129.2, 128.7, 127.3, 121.0, 116.0, 113.9, 60.8, 55.3, 37.9, 37.3. (c 1.0, CHCl3). HPLC conditions: Chiralcel OD-3 column (25 cm × 0.46 cm ID); n-hexane / 2-propanol = 90:10; temperature, room temperature, flow rate = 1.0 mL / min; 220 nm UV detector; t R (R) = 19.48 min; t R (S)=11.40min.HRMS(ESI)Calcd for C 16 H 22 NO3([M+NH4] + ):276.1594,Found:276.1586.

[0129] Example 23:

[0130] The racemic substrate rac-1m (1.0 mmol), catalyst (R)-4e (1.0 mg, 0.001 mmol), t-BuOK (0.12 g, 1.0 mmol), and MeOH (2.0 mL) were added to a 20 mL autoclave. The autoclave was pressurized with hydrogen to 5 atm three times and then to 10 atm. The reaction mixture was stirred at room temperature (25°C–30°C) until no significant pressure drop was observed. The reaction mixture was then quenched with 1N HCl (2 mL) and extracted three times with ethyl acetate (5 mL x 3). The combined organic phases were washed with brine, dried over anhydrous MgSO₄, and concentrated under reduced pressure. The concentrate was purified by column chromatography (eluent: ethyl acetate / petroleum ether (v / v = 1:10–1:4)) to afford (S)-2m (yield 47%, 94.7% ee) and (R)-3m (yield 50%, 91.0% ee). Characterization data of (S)-2m: colorless oil, 47% yield, 94.7% ee. 1H NMR(400MHz, CDCl3)δ:7.26-7.24(m,2H),7.20-7.18(m,2H),7.16-7.07(m,1H),7.01(dd,J=7.8,1. 7Hz,1H),6.94-6.75(m,2H),5.80(s,1H),4.84(t,J=7.7Hz,1H),3.63(s,3H),3.10(d,J=7.7Hz,2H). 13 C NMR (100MHz, CDCl3) δ: 173.6, 153.4, 141.6, 132.4, 130.1, 129.4, 128.7, 128.3, 128.1, 121.3, 117.0, 100.1, 52.2, 39.6, 39.4. (c 1.0, MeOH). HPLC conditions: chiral column (25 cm × 0.46 cm ID); n-hexane / 2-propanol = 93:7; temperature, room temperature, flow rate = 1.0 mL / min; 210 nm UV detector; t R (S) = 12.55 min; t R (R)=19.69min.HRMS(ESI)Calcd for C 16 H 16 ClO3([M+H] + ):291.0782,Found:291.0779. Characterization data of (R)-3m: white solid, mp 102-103 ° C, 131 mg, 50% yield, 91.0% ee. 1 H NMR (400MHz, CDCl3) δ: 7.23 (q, J = 8.4Hz, 4H), 7.07 (t, J = 7.7Hz, 1H), 6.94-6.93 (m, 1H), 6.86-6.80 (m, 2H), 6.68 (s, 1H), 4.58 (d d,J=10.0,5.9Hz,1H),3.75(dt,J=10.5,5.0Hz,1H),3.53(td,J=10.0,4.3Hz,1H),2.51(s,1H),2.38-2.29(m,1H),2.13(m,1H). 13 CNMR(100MHz, CDCl3)δ:153.8,142.7,132.1,130.4,129.7,128.8,128.6,127.7,121.4,116.3,60.7,38.2,37.0. (c 1.0, MeOH). HPLC conditions: chiral column (25 cm × 0.46 cm ID); n-hexane / 2-propanol = 90:10; temperature, room temperature, flow rate = 1.0 mL / min; 220 nm UV detector; t R (R) = 5.87 min; t R (S)=8.04min.HRMS(ESI)Calcd for C 17 H 21 O2([M+H] + ):263.0833,Found:263.0829.

[0131] Example 24:

[0132] The racemic substrate rac-1n (1.0 mmol), catalyst (R)-4e (1.0 mg, 0.001 mmol), t-BuOK (0.12 g, 1.0 mmol), and MeOH (2.0 mL) were added to a 20 mL autoclave. The autoclave was pressurized with hydrogen to 5 atm three times and then to 10 atm. The reaction mixture was stirred at room temperature (25°C–30°C) until no significant pressure drop was observed. The reaction mixture was then quenched with 1N HCl (2 mL) and extracted three times with ethyl acetate (5 mL x 3). The combined organic phases were washed with brine, dried over anhydrous MgSO₄, and concentrated under reduced pressure. The concentrate was purified by column chromatography (eluent: ethyl acetate / petroleum ether (v / v = 1:10–1:4)) to afford (R)-2n (yield 50%, 90.5% ee) and (S)-3n (yield 47%, 97.0% ee). Characterization data of (R)-2n: colorless oil, 143 mg, 50% yield, 90.5% ee. 1 H NMR (400MHz, CDCl3) δ7.24 (dd, J=7.5, 1.7Hz, 1H), 7.21-7.12 (m, 2H), 7.06 (td, J=7.5, 1.7Hz, 1H), 6.93 (td ,J=7.5,1.1Hz,1H),6.86-6.81(m,4H),5.11(t,J=7.8Hz,1H),3.85(s,3H),3.58(s,3H),3.19-3.08(m,2H). 13 C NMR (100MHz, CDCl3) δ173.0,155.9,154.0,131.1,129.4,127.9,127.8,127.4,127.1,121.5,120.8,117.0,111.2,56.0,52.0,39.0,32.3. (c 1.0, MeOH). HPLC conditions: chiral column (25 cm × 0.46 cm ID); n-hexane / 2-propanol = 90:10; temperature, room temperature, flow rate = 1.0 mL / min; 220 nm UV detector; t R (R) = 4.62 min; t R (S)=5.42min.HRMS(ESI)Calcd forC 17 H 19 O4([M+H] + ):287.1278,Found:287.1273. Characterization data of (S)-3n: white solid, mp 105-106 ° C, 121 mg, 47% yield, 97.0% ee. 1 H NMR (400MHz, CDCl3) δ7.28 (dd, J=7.6, 1.7Hz, 1H), 7.20-7.13 (m, 2H), 7.04 (td, J=7.7, 1.7Hz, 1H), 6.95 (td, J= 7.6,1.2Hz,1H),6.88-6.78(m,3H),4.77(t,J=7.8Hz,1H),3.79(s,3H),3.63-3.50(m,2H),2.32-2.24(m,2H). 13 C NMR (101MHz, CDCl3) δ156.1,154.2,132.1,130.2,127.7,127.6,127.4,127.3,121.6,120.8,116.4,111.0,60.8,56.0,36.8,31.5. (c 1.0, MeOH). HPLC conditions: chiral column (25 cm × 0.46 cm ID); n-hexane / 2-propanol = 90:10; temperature, room temperature, flow rate = 1.0 mL / min; 220 nm UV detector; t R (R) = 39.65 min; t R (S)=42.12min.HRMS(ESI)Calcd for C 16 H 19 O3([M+H] + ):259.1329,Found:259.1327.

[0133] Example 25:

[0134] The racemic substrate rac-1o (1.0 mmol), catalyst (R)-4e (1.0 mg, 0.001 mmol), t-BuOK (0.12 g, 1.0 mmol), and MeOH (2.0 mL) were added to a 20 mL autoclave. The autoclave was pressurized to 5 atm with hydrogen three times and then to 10 atm. The reaction mixture was stirred at room temperature (25°C–30°C) until no significant pressure drop was observed. The reaction mixture was then quenched with 1N HCl (2 mL) and extracted three times with ethyl acetate (5 mL x 3). The combined organic phases were washed with brine, dried over anhydrous MgSO₄, and concentrated under reduced pressure. The concentrate was purified by column chromatography (eluent: ethyl acetate / petroleum ether (v / v = 1:10–1:4)) to afford (S)-2o (yield 46%, 96.3% ee) and (R)-3o (yield 51%, 86.6% ee). Characterization data of (S)-2o: colorless oil, 138 mg, 46% yield, 96.3% ee. 1 H NMR (400MHz, CDCl3) δ: 7.17 (d, J = 8.6 Hz, 2H), 6.91-6.79 (m, 4H), 6.73 (d, J = 8.1 Hz, 1H), 5.71 (s,1H),4.75(t,J=7.7Hz,1H),3.78(s,3H),3.63(s,3H),3.08(d,J=7.7Hz,2H),2.20(s,3H). 13 C NMR (100MHz, CDCl3) δ: 173.9, 158.3, 151.1, 135.1, 130.7, 130.4, 128.9, 128.8, 128.4, 117.2, 114.1, 55.4, 52.2, 40.1, 39.0, 20.9. (c 1.0, MeOH). HPLC conditions: chiral column (25 cm × 0.46 cm ID); n-hexane / 2-propanol = 90:10; temperature, room temperature, flow rate = 1.0 mL / min; 210 nm UV detector; t R (S) = 9.55 min; t R (R)=17.87min.HRMS(ESI)Calcd for C 18 H 21 O4([M+H] + ):301.1434,Found:301.1429. Characterization data of (R)-3o: white solid, mp 105-106 ° C, 138 mg, 51% yield, 86.6% ee. 1HNMR(400MHz, CDCl3)δ:7.24-7.16(m,2H),6.90-6.81(m,3H),6.77(s,1H),6.73-6.70(m,1H),6.04(s,1H),4.48(dd,J=9.9,6 .2Hz,1H),3.79(s,3H),3.75-3.69(m,1H),3.56-3.50(m,1H),2.38-2.29(m,1H),2.19(s,3H),2.18-2.10(m,1H),2.06(s,1H). 13 C NMR (100MHz, CDCl3) δ: 158.1, 151.6, 136.2, 130.9, 130.3, 129.3, 129.2, 128.0, 116.2, 114.0, 60.9, 55.4, 38.1, 37.4, 20.9. (c1.0, MeOH). HPLC conditions: chiral column (25 cm × 0.46 cm ID); n-hexane / 2-propanol = 90:10; temperature, room temperature, flow rate = 1.0 mL / min; 220 nm UV detector; t R (S) = 19.91 min; t R (R)=22.74min.HRMS(ESI)Calcd for C 17 H 21 O3([M+H] + ):273.1485,Found:273.1480.

[0135] Example 26:

[0136] The racemic substrate rac-1p (1.0 mmol), catalyst (R)-4e (1.0 mg, 0.001 mmol), t-BuOK (0.12 g, 1.0 mmol), and MeOH (2.0 mL) were added to a 20 mL autoclave. The autoclave was pressurized with hydrogen to 5 atm three times and then to 10 atm. The reaction mixture was stirred at room temperature (25°C–30°C) until no significant pressure drop was observed. The reaction mixture was then quenched with 1N HCl (2 mL) and extracted three times with ethyl acetate (5 mL x 3). The combined organic phases were washed with brine, dried over anhydrous MgSO₄, and concentrated under reduced pressure. The concentrate was purified by column chromatography (eluent: ethyl acetate / petroleum ether (v / v = 1:10–1:4)) to afford (S)-2p (yield 47%, 95.4% ee) and (R)-3p (yield 50%, 90.4% ee). Characterization data of (S)-2p: white solid, mp 113-114°C, 149 mg, 47% yield, 95.4% ee. 1 H NMR(400MHz, CDCl3)δ:7.22-7.12(m,2H),6.89-6.77(m,3H),6.69-6.54(m,2H),5.69(s, 1H), 4.77 (t, J = 7.7Hz, 1H), 3.77 (s, 3H), 3.69 (s, 3H), 3.64 (s, 3H), 3.08 (d, J = 7.7Hz, 2H). 13 C NMR (100MHz, CDCl3) δ: 173.9, 158.4, 154.0, 147.4, 134.8, 132.3, 128.9, 118.0, 114.4, 114.1, 112.2, 55.7, 55.3, 52.2, 40.0, 39.1. (c 1.0, MeOH). HPLC conditions: chiral column (25 cm × 0.46 cm ID); n-hexane / 2-propanol = 90:10; temperature, room temperature, flow rate = 1.0 mL / min; 220 nm UV detector; t R (S) = 11.38 min; t R (R)=17.25min.HRMS(ESI)Calcd for C 18 H 21 O5([M+H] + ):317.1384,Found:317.1378. Characterization data of (R)-3p: white solid, mp 126-127 ° C, 144 mg, 50% yield, 90.4% ee. 1HNMR (400MHz, CDCl3) δ: 7.21 (d, J = 8.7Hz, 2H), 6.97-6.81 (m, 2H), 6.78 (d, J = 8.7Hz, 1H), 6.63 (dd, J = 8.7, 3.1Hz, 1H), 6.56 (d, J = 3.0Hz, 1H), 5.77 (s, 1H),4.49(dd,J=9.8,6.1Hz,1H),3.79(s,3H)3.77-3.74(m,1H),3.68(s,3 H),3.57-3.51(m,1H),2.37-2.29(m,1H),2.17-2.05(m,1H),1.62(s,1H). 13 C NMR (100MHz, CDCl3) δ: 158.2, 154.0, 147.8, 135.9, 132.6, 129.2, 117.0, 114.8, 114.0, 111.8, 60.8, 55.7, 55.4, 38.3, 37.2. (c 1.0, MeOH). HPLC conditions: chiral column (25 cm × 0.46 cm ID); n-hexane / 2-propanol = 90:10; temperature, room temperature, flow rate = 1.0 mL / min; 220 nm UV detector; t R (R) = 10.16 min; t R (S) = 13.5 min.

[0137] Example 27:

[0138] The racemic substrate rac-1q (1.0 mmol), catalyst (R)-4e (1.0 mg, 0.001 mmol), t-BuOK (0.12 g, 1.0 mmol), and MeOH (2.0 mL) were added to a 20 mL autoclave. The autoclave was pressurized to 5 atm with hydrogen three times and then to 10 atm. The reaction mixture was stirred at room temperature (25°C–30°C) until no significant pressure drop was observed. The reaction mixture was then quenched with 1N HCl (2 mL) and extracted three times with ethyl acetate (5 mL x 3). The combined organic phases were washed with brine, dried over anhydrous MgSO₄, and concentrated under reduced pressure. The concentrate was purified by column chromatography (eluent: ethyl acetate / petroleum ether (v / v = 1:10–1:4)) to afford (S)-2q (yield 47%, 89.6% ee) and (R)-3q (yield 50%, 87.0% ee). Characterization data of (S)-2q: colorless oil, 162 mg, 47% yield, 89.6% ee. 1H NMR (400MHz, CDCl3) δ: 7.15 (d, J = 8.3Hz, 2H), 6.80 (dd, J = 13.1, 8.5Hz, 3H), 6.66-6.56 (m, 2H), 5.69 (s, 1H), 4.75 (t, J = 7.7 Hz,1H),3.88(t,J=6.5Hz,2H),3.69(s,3H),3.64(s,3H),3.07(d,J=7.7Hz,2H),1.82–1.74(m,2H),1.02(t,J=7.4Hz,3H). 13 C NMR (100MHz, CDCl3) δ: 174.0, 158.0, 154.0, 147.4, 134.6, 132.4, 128.8, 118.1, 114.8, 114.4, 112.3, 69.6, 55.7, 52.2, 40.1, 39.1, 22.7, 10.7. (c 1.0, MeOH). HPLC conditions: chiral column (25 cm × 0.46 cm ID); n-hexane / 2-propanol = 90:10; temperature, room temperature, flow rate = 1.0 mL / min; 210 nm UV detector; t R (R) = 16.69 min; t R (S) = 20.83 min. Characterization data of (R)-3q: colorless oil, 158 mg, 50% yield, 87.0% ee. 1 H NMR(400MHz, CDCl3)δ:7.22-7.14(m,2H),6.87-6.81(m,2H),6.77(d,J=8.7Hz,1H),6 .61(dd,J=8.7,3.1Hz,1H),6.55(d,J=3.1Hz,1H),6.06(s,1H),4.48(dd,J=9.8,6.1Hz ,1H),3.89(t,J=6.6Hz,2H),3.76(dd,J=10.6,5.1Hz,1H),3.67(s,3H),3.56-3.49(m ,1H),2.36-2.28(m,1H),2.16-2.08(m,2H),1.83-1.74(m,2H),1.02(t,J=7.4Hz,3H). 13 C NMR (100MHz, CDCl3) δ: 157.8, 154.0, 147.9, 135.5, 132.5, 129.2, 117.2, 114.8, 114.7, 111.9, 69.6, 60.9, 55.7, 38.5, 37.2, 22.8, 10.7. (c 1.0, MeOH). HPLC conditions: chiral column (25 cm × 0.46 cm ID); n-hexane / 2-propanol = 90:10; temperature, room temperature, flow rate = 1.0 mL / min; 220 nm UV detector; t R (R) = 9.66 min; t R (S)=17.72min.HRMS(ESI)Calcd for C 19 H 25 O4([M+H] + ):317.40455,Found:317.4041.

Claims

1. A method for the asymmetric catalytic hydrogenation of racemic β-aryl esters or lactones, characterized in that: Further used in the preparation of drugs or natural product intermediates, Wherein, R is aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkyl or cyclic alkyl; R 2 is an alkyl group; X is hydrogen, an alkyl group, an alkoxy group, a halogen group or a carboxylate group.

2. The asymmetric catalytic hydrogenation method according to claim 1, characterized in that The asymmetric hydrogenation method is: Wherein, X is hydrogen, alkyl, alkoxy, halogen or carboxylate.

3. The asymmetric catalytic hydrogenation method according to claim 2, characterized in that The prepared (S)-2 compound is used to prepare the intermediate general structure 21, Wherein, X is hydrogen, alkyl, alkoxy, halogen or carboxylate.

4. The asymmetric catalytic hydrogenation method according to claim 2, characterized in that The specific structure of the prepared (S)-2 compound (S)-2p is used to prepare the intermediate (S)-23.

5. The asymmetric catalytic hydrogenation method according to claim 3, characterized in that For the preparation of intermediate 21, 6. The asymmetric catalytic hydrogenation method according to claim 1, characterized in that Further preparing tolterodine, 7. The asymmetric catalytic hydrogenation method according to claim 1, characterized in that Further prepare the intermediate (S)-3g or (R)-3g of methoxydalbergiaquinone, 8. The asymmetric catalytic hydrogenation method according to claim 1, characterized in that Further preparation of intermediates for AM-1638 (S)-16 compound, 9. The asymmetric catalytic hydrogenation method according to claim 1, characterized in that Further preparing the intermediate (S)-18 compound of AMG-837 compound, 10. A method for preparing fesoterodine, characterized in that: Prepare the compound of formula (R)-2, The specific compound (R)-2e is further prepared to obtain fesoterodine, 11. The asymmetric catalytic hydrogenation method according to claim 2 or 5, characterized in that: The prepared (S)-2q compound is used to prepare Enlasentan.

12. The asymmetric catalytic hydrogenation method according to claim 2 or 4, characterized in that The prepared (S)-2p compound is further used to prepare the intermediate (S)-24 compound based on the resveratrol oligomer pallidol, (+)-quadragularin A and (+)-isopaucifloral F.

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