OXA-SPIRODIPHOSPHINE LIGAND AND METHOD FOR ASYMMETRIC HYDROGENATION OF alpha, beta-UNSATURATED CARBOXYLIC ACIDS

Abstract

The present invention provides an oxa-spirodiphosphine ligand having a structure of general Formula (I) below:

##STR00001##

wherein in general Formula (I), R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are the same, and are alkyl, alkoxy, aryl, aryloxy, or hydrogen, in which R.sup.1, R.sup.2, R.sup.3 and R.sup.4 may or may not form a ring, any two of them may form a ring, or a polycyclic ring may be formed between two pairs of them; R.sup.5 and R.sup.6 is alkyl, aryl, or hydrogen; and R.sup.7 and R.sup.8 is alkyl, benzyl, or aryl. The present invention also provides a method for asymmetric hydrogenation of α,β-unsaturated carboxylic acids. A complex of the oxa-spirodiphosphine ligand with ruthenium shows excellent activity and enantioselectivity in the asymmetric hydrogenation of various α,β-unsaturated carboxylic acids, with which a chiral carboxylic acid product can be obtained with an enantioselectivity up to 99%.

Claims

1. An oxa-spirodiphosphine ligand, having a structure of general Formula (I) below: ##STR00022## wherein in general Formula (I): R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are the same, and are all alkyl, alkoxy, aryl, aryloxy, or hydrogen, where R.sup.1, R.sup.2, R.sup.3 and R.sup.4 may or may not form a ring, any two of them may form a ring, or a polycyclic ring may be formed between two pairs of them; R.sup.5 and R.sup.6 are alkyl, aryl, or hydrogen; and R.sup.7 and R.sup.8 are alkyl, benzyl, or aryl.

2. The oxa-spirodiphosphine ligand according to claim 1, which is the (±)-oxa-spirodiphosphine ligand, the (+)-oxa-spirodiphosphine ligand, or the (−)-oxa-spirodiphosphine ligand.

3. The oxa-spirodiphosphine ligand according to claim 1, comprising a compound having a structure below: ##STR00023## ##STR00024## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are the same or different substituents, and include hydrogen, alkyl, fluoroalkyl, aryl, or alkoxy; and Ar is alkyl, benzyl or aryl.

4. The oxa-spirodiphosphine ligand according to claim 2, comprising a compound having a structure below: ##STR00025## ##STR00026## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are the same or different substituents, and include hydrogen, alkyl, fluoroalkyl, aryl, or alkoxy; and wherein Ar is alkyl, benzyl or aryl.

5. The oxa-spirodiphosphine ligand according to claim 3, wherein Ar is phenyl, or phenyl substituted with alkyl or alkoxy: ##STR00027##

6. The oxa-spirodiphosphine ligand according to claim 4, wherein Ar is phenyl, or phenyl substituted with alkyl or alkoxy: ##STR00028##

7. A method for asymmetric hydrogenation of α,β-unsaturated carboxylic acids, comprising the steps of: preparing a diphosphine ruthenium acetate complex by using the oxa-spirodiphosphine ligand according to claim 1; and achieving asymmetric hydrogenation of α,β-unsaturated carboxylic acids by placing the diphosphine ruthenium acetate complex in an organic solvent, wherein the organic solvent is methanol, ethanol, trifluoroethanol, hexafluoroisopropanol, tetrahydrofuran, dioxane, toluene, benzene, methylene chloride, dichloroethane, methyl tert-butyl ether, diethyl ether or carbon tetrachloride.

8. The method according to claim 7, wherein the diphosphine ruthenium acetate complex is a compound having a structure below: ##STR00029## wherein R=alkyl, fluoroalkyl or aryl.

9. The method according to claim 7, wherein the diphosphine ruthenium acetate complex comprises a product obtained by a synthesis route below: ##STR00030## wherein R=alkyl, fluoroalkyl or aryl; or is ##STR00031## in which R=alkyl, fluoroalkyl or aryl.

10. The method according to claim 7, wherein the diphosphine ruthenium acetate complex is used in the asymmetric reduction of a Sacubitril intermediate: ##STR00032## where R.sup.1 is the Boc, Ts, N.sub.S, Bn, PMB, PMP or Bz protecting group, R.sup.2 is H, alkyl, or a substituted alkyl or aryl group, in which the ligand used is Compound 1 ##STR00033## and wherein the catalyst is used in an amount of substrate S/catalyst C=1 to 30000.

11. The method according to claim 7, wherein the diphosphine ruthenium acetate complex is used in the asymmetric reduction of a Sacubitril intermediate: ##STR00034## where R.sup.1 is the Boc, Ts, N.sub.S, Bn, PMB, PMP or Bz protecting group, R.sup.2 is H, alkyl, or a substituted alkyl or aryl group, in which the ligand used is Compound 1a ##STR00035## and wherein the catalyst is used in an amount of substrate S/catalyst C=1 to 30000.

12. The method according to claim 7, wherein the diphosphine ruthenium acetate complex is used in the asymmetric reduction of the intermediates of the antidepressants Paroxetine and Femoxetine: ##STR00036## where R.sup.1 is the Boc, Ts, N.sub.S, Bn, PMB, PMP or Bz protecting group, R.sup.2 is H, alkyl, or a substituted alkyl or aryl group, in which the ligand used is 1 ##STR00037## and wherein the catalyst is used in an amount of substrate S/catalyst C=1 to 30000.

13. The method according to claim 7, wherein the diphosphine ruthenium acetate complex is used in the asymmetric reduction of the intermediates of the antidepressants Paroxetine and Femoxetine: ##STR00038## where R.sup.1 is the Boc, Ts, N.sub.S, Bn, PMB, PMP or Bz protecting group, R.sup.2 is H, alkyl, or a substituted alkyl or aryl group, in which the ligand used is (R)-1a: ##STR00039## and wherein the catalyst is used in an amount of substrate S/catalyst C=1 to 30000.

14. The method according to claim 7, wherein the oxa-spirodiphosphine ligand is used as a catalyst in a reaction route shown below: ##STR00040## where R.sub.1, R.sub.2 and R.sub.3=alkyl, fluoroalkyl or aryl, alkoxy, and aryloxy; X is O, N, or S heteroatom, and n=0-10, in which the ligand used is 1 ##STR00041## and wherein the catalyst is used in an amount of substrate S/catalyst C=1 to 30000.

15. The method according to claim 7, wherein the oxa-spirodiphosphine ligand is used as a catalyst in a reaction route shown below: ##STR00042## where R.sub.1, R.sub.2 and R.sub.3=alkyl, fluoroalkyl or aryl, alkoxy, and aryloxy; X is O, N, or S heteroatom, and n=0-10, in which the ligand used is (R)-1a: ##STR00043## and wherein the catalyst is used in an amount of substrate S/catalyst C=1 to 30000.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0027] FIG. 1 is a schematic view showing the present oxa-spirodiphosphine ligand O-SDP, preparation of various chiral compounds in the preparation of α,β-unsaturated carboxylic acids, and the corresponding conversion rates and enantioselectivity ee.

[0028] FIG. 2 is a schematic view showing the present oxa-spirodiphosphine ligand O-SDP, preparation of various chiral compounds in the preparation of α,β-unsaturated carboxylic acids, and the corresponding conversion rates and enantioselectivity ee.

[0029] FIG. 3 is a schematic view showing the present oxa-spirodiphosphine ligand O-SDP, and the use of the chiral compounds prepared in the preparation of α,β-unsaturated carboxylic acids, in the synthesis of biologically active molecules.

DESCRIPTION OF THE EMBODIMENTS

[0030] The present invention will be described below by way of examples with reference to accompanying drawings. However, the oxa-spirodiphosphine ligand O-SDP and the method for asymmetric hydrogenation of α,β-unsaturated carboxylic acids provided in the present invention are not limited thereto.

[0031] In the field of chiral synthesis technology, although O-SDP is similar in structure to SDP, O-SDP has a very unique structure where the angle of engagement is 99.2 degrees, which is greater than that of the known common chiral diphosphine ligands such as BINAP, MeO-BiPHEP, and Segphos, etc. A complex of the ligand with ruthenium shows excellent activity and enantioselectivity in the asymmetric hydrogenation of various α,β-unsaturated carboxylic acids, with which a chiral carboxylic acid product can be obtained with an enantioselectivity up to 99%. The synthesis method by means of this route is applicable to the construction of core skeletons of chemical molecules with important biological activities such as Paroxetine, Femoxetine, nipecotic acid and Sacubitril.

[0032] The reaction principle is as follows.

##STR00018##

[0033] a (R)-1e is used as a ligand, TFE is used as a solvent, and the reaction time is 10 hrs.

##STR00019##

[0034] Yield represents the yield of the product.

##STR00020## ##STR00021##

Example 1

Preparation of the Catalyst Ru(1a)OAc.SUB.2

[0035] Under a N.sub.2 atmosphere, [RuPhCl.sub.2].sub.2 (25 mg, 0.05 mmol) and the ligand 1a (61 mg, 0.103 mmol) were added to a 10 mL one-neck flask, and then DMF (2 mL) were added. The reaction was continued at 100° C. for 3 h. After cooling to room temperature, 1.5 mL of a solution of anhydrous sodium acetate (0.111 g, 1.3 mmol) in methanol was added. After 20 min, deoxygenated deionized water was added. A gray solid was precipitated from the reaction system, and filtered out. The solvent and water were removed under reduced pressure to obtain the catalyst Ru(1a)OAc.sub.2 (57 mg, yield=71%).

Example 2

Preparation of Catalyst Ru(1a)(CF.SUB.3.CO).SUB.2

[0036] Under a N.sub.2 atmosphere, bis(2-methylallyl)-cycloocta-1,5-diene ruthenium (32 mg, 0.05 mmol) and the ligand 1a (61 mg, 0.103 mmol) were added to a 10 mL one-neck flask, and then acetone (2 mL) were added. The reaction was continued at 40° C. for 0.5 h. Then, trifluoroacetic acid (33 mg, 0.3 mmol) was added and stirred overnight at 40° C. The solvent was removed under reduced pressure, and then petroleum ether (1 mL) was added, and filtered to obtain the target product Ru(1a)(CF.sub.3CO).sub.2 (81 mg, yield=88%).

Example 3

Synthesis of (3R,4R)-1-(t-butoxycarbonyl)-4-phenyl-3-carboxylic acid 3a

[0037] Under a N.sub.2 atmosphere, 2a (0.1 mmol), the catalyst Ru(1a)OAc.sub.2 (0.8 mg, 0.001 mmol), and methanol (1 mL) were added to a hydrogenation flask. After 24 h under a hydrogen atmosphere of 60 atm, the raw material was completely converted into a product. 29.0 mg, yield of product=95%, >99% ee, [a].sup.25.sub.D=+38.0 (c=0.5, CHCl.sub.3), yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.29-7.24 (m, 2H, Ar), 7.23-7.17 (m, 3H, Ar), 4.44 (d, J=12.7 Hz, 1H, CH.sub.2), 4.26 (d, J=9.0 Hz, 1H, CH.sub.2), 3.16 (d, J=11.1 Hz, 1H, CH), 3.01-2.82 (m, 3H, CH.sub.2), 2.55 (dt, J=12.0, 8.6 Hz, 1H, CH), 1.68 (dd, J=13.0, 2.8 Hz, 1H, CH.sub.2), 1.39 (s, 9H, CH.sub.3). .sup.13C NMR (101 MHz, CDCl.sub.3) δ 176.9, 154.7, 142.1, 128.3, 127.4, 126.6, 79.8, 46.1, 45.2, 43.8, 43.0, 28.2, 25.6. HRMS (ESI) calcd. for C.sub.17H.sub.22NO.sub.4 [M-H].sup.−: 304.1554, Found: 304.1556. HPLC conditions: Daicel AD-3, volume of injection: 2 μL (c=1 mg/mL), Hexane/IPA=97/3, 1.0 mL/Min, 208 nm, t.sub.R (major)=29.6 Min, t.sub.R (minor)=31.4 Min.

Example 4

Synthesis of (3R,4R)-1-(t-butoxycarbonyl)-4-p-methylphenyl-3-carboxylic acid 3b

[0038] Under a N.sub.2 atmosphere, 2b (0.1 mmol), the catalyst Ru(1a)OAc.sub.2 (0.8 mg, 0.001 mmol), and methanol (1 mL) were added to a hydrogenation flask. After 24 h under a hydrogen atmosphere of 60 atm, the raw material was completely converted into a product. 31.0 mg, yield of product=97%, >99% ee, [a].sup.25.sub.D=+47.1 (c=0.5, CHCl.sub.3), yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.09 (q, J=8.2 Hz, 4H, Ar), 4.42 (d, J=13.2 Hz, 1H, CH.sub.2), 4.24 (d, J=10.5 Hz, 1H, CH.sub.2), 3.15 (d, J=11.8 Hz, 1H, CH), 3.00-2.78 (m, 3H, CH.sub.2), 2.61-2.42 (m, 1H, CH), 2.30 (s, 3H, CH.sub.3), 1.67 (dd, J=13.1, 2.9 Hz, 1H, CH.sub.2), 1.40 (s, 9H, CH.sub.3). .sup.13C NMR (101 MHz, CDCl.sub.3) δ 177.0, 154.7, 139.1, 136.1, 129.0, 127.2, 79.8, 46.0, 45.3, 43.9, 42.6, 28.2, 25.8, 20.9. HRMS (ESI) calcd. for C.sub.18H.sub.24NO.sub.4 [M-H].sup.−: 318.1711, Found: 318.1713. HPLC conditions: Daicel AD-3, volume of injection: 2 μL (c=1 mg/mL), Hexane/IPA=97/3, 1.0 mL/Min, 220 nm, t.sub.R(major)=18.9 Min, t.sub.R (minor)=21.9 Min.

Example 5

Synthesis of (3R,4R)-1-(t-butoxycarbonyl)-4-p-methoxyphenyl-3-carboxylic acid 3c

[0039] Under a N.sub.2 atmosphere, 2c (0.1 mmol), the catalyst Ru(1a)OAc.sub.2 (0.8 mg, 0.001 mmol), and methanol (1 mL) were added to a hydrogenation flask. After 24 h under a hydrogen atmosphere of 60 atm, the raw material was completely converted into a product. 32.2 mg, yield of product=96%, 99% ee, [a].sup.25.sub.D=+29.5 (c=0.5, CHCl.sub.3), yellow solid. .sup.1H NMR (400 MHz, CDCl3) δ 7.14 (d, J=8.7 Hz, 2H, Ar), 6.84-6.78 (m, 2H, Ar), 4.41 (d, J=13.6 Hz, 1H, CH.sub.2), 4.24 (d, J=10.7 Hz, 1H, CH.sub.2), 3.77 (s, 3H, CH.sub.3), 3.14 (d, J=11.4 Hz, 1H, CH), 2.97-2.79 (m, 3H, CH.sub.2), 2.51 (qd, J=12.2, 3.8 Hz, 1H, CH), 1.66 (dd, J=13.1, 2.9 Hz, 1H, CH.sub.2), 1.40 (s, 9H, CH.sub.3). .sup.13C NMR (101 MHz, CDCl3) δ 176.9, 158.2, 154.7, 134.2, 128.4, 113.7, 79.8, 55.1, 45.9, 45.4, 43.9, 42.2, 28.2, 25.9. HRMS (ESI) calcd. for C.sub.18H.sub.24NO.sub.5 [M-H].sup.−: 334.1660, Found: 334.1662. HPLC conditions: Daicel AS-3, volume of injection: 2 μL (c=1 mg/mL), Hexane/IPA=97/3, 1.0 mL/Min, 230 nm, t.sub.R (major)=16.5 Min, t.sub.R (minor)=19.2 Min.

Example 6

Synthesis of (3R,4R)-1-(t-butoxycarbonyl)-4-p-chlorophenyl-3-carboxylic acid 3d

[0040] Under a N.sub.2 atmosphere, 2d (0.1 mmol), the catalyst Ru(1a)OAc.sub.2 (0.8 mg, 0.001 mmol), and methanol (1 mL) were added to a hydrogenation flask. After 24 h under a hydrogen atmosphere of 60 atm, the raw material was completely converted into a product. 33.6 mg, yield of product=99%, 98% ee, [a].sup.25.sub.D=+47.9 (c=0.5, CHCl.sub.3), white solid. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.26 (d, J=8.3 Hz, 2H, Ar), 7.16 (d, J=8.3 Hz, 2H, Ar), 4.48 (d, J=12.0 Hz, 1H, CH.sub.2), 4.29 (d, J=9.8 Hz, 1H, CH.sub.2), 3.14 (d, J=11.6 Hz, 1H, CH), 2.93 (ddd, J=42.0, 23.0, 10.6 Hz, 3H, CH.sub.2), 2.53 (dd, J=20.9, 11.7 Hz, 1H), 1.68 (d, J=11.0 Hz, 1H, CH.sub.2), 1.40 (s, 9H, CH.sub.3). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 175.9, 154.7, 140.6, 132.5, 128.8, 128.5, 80.0, 46.1, 45.1, 43.8, 42.4, 28.3, 25.5. HRMS (ESI) calcd. for C.sub.17H.sub.21ClNO.sub.4 [M-H].sup.−: 338.1165, Found: 338.1169. HPLC conditions: Daicel AS-3, volume of injection: 2 μL (c=1 mg/mL), Hexane/IPA=97/3, 1.0 mL/Min, 208 nm, t.sub.R (major)=9.0 Min, t.sub.R (minor)=10.0 Min.

Example 7

Synthesis of (3R,4R)-1-(t-butoxycarbonyl)-4-p-fluorophenyl-3-carboxylic acid 3e

[0041] Under a N.sub.2 atmosphere, 2e (0.1 mmol), the catalyst Ru(1a)OAc.sub.2 (0.8 mg, 0.001 mmol), and methanol (1 mL) were added to a hydrogenation flask. After 24 h under a hydrogen atmosphere of 60 atm, the raw material was completely converted into a product. 31.4 mg, yield of product=97%, 99% ee, [a].sup.25.sub.D=+35.2 (c=0.5, CHCl.sub.3), yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.18 (dd, J=8.4, 5.4 Hz, 2H, Ar), 6.96 (t, J=8.7 Hz, 2H, Ar), 4.45 (d, J=12.9 Hz, 1H, CH.sub.2), 4.28 (d, J=9.3 Hz, 1H, CH.sub.2), 3.14 (d, J=10.9 Hz, 1H, CH), 2.99-2.80 (m, 3H, CH.sub.2), 2.53 (dd, J=20.9, 12.0 Hz, 1H, CH), 1.66 (dd, J=13.0, 2.5 Hz, 1H, CH.sub.2), 1.39 (s, 9H, CH.sub.3). .sup.13C NMR (101 MHz, CDCl3) δ 176.8, 161.6 (d, J=243.5 Hz), 154.7, 137.8 (d, J=2.9 Hz), 128.9 (d, J=7.9 Hz), 115.1 (d, J=20.9 Hz), 79.9, 46.0, 45.4, 43.8, 42.3, 28.2, 25.7. .sup.19F NMR (376 MHz, CDCl3) δ −116.3. HRMS (ESI) calcd. for C.sub.17H.sub.21FNO.sub.4 [M-H].sup.−: 322.1460, Found: 322.1464. HPLC conditions: Daicel AS-3, volume of injection: 2 μL (c=1 mg/mL), Hexane/IPA=98/2, 0.8 mL/Min, 208 nm, t.sub.R (major)=15.0 Min, t.sub.R (minor)=19.6 Min.

Example 8

Synthesis of (3R,4R)-1-(t-butoxycarbonyl)-4-m-methoxyphenyl-3-carboxylic acid 3f

[0042] Under a N.sub.2 atmosphere, 2f (0.1 mmol), the catalyst Ru(1a)OAc.sub.2 (0.8 mg, 0.001 mmol), and methanol (1 mL) were added to a hydrogenation flask. After 24 h under a hydrogen atmosphere of 60 atm, the raw material was completely converted into a product. 32.2 mg, yield of product=96%, 98% ee, [a].sup.25.sub.D=+50.3 (c=0.5, CHCl3), yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.18 (t, J=7.9 Hz, 1H, Ar), 6.84-6.72 (m, 3H, Ar), 4.43 (d, J=12.9 Hz, 1H, CH.sub.2), 4.24 (d, J=11.1 Hz. 1H, CH.sub.2), 3.74 (s, 3H, CH.sub.3), 3.15 (d, J=11.0 Hz, 1H, CH.sub.3), 3.00-2.82 (m, 3H, CH.sub.2), 2.53 (dt, J=20.7, 10.2 Hz, 1H, CH), 1.68 (dd, J=12.9, 2.5 Hz, 1H, CH.sub.2), 1.40 (s, 9H, CH.sub.3). .sup.13C NMR (101 MHz, CDCl.sub.3) δ 176.6, 159.5, 154.7, 143.8, 129.3, 119.7, 113.3, 112.0, 79.8, 55.0, 46.0, 45.2, 44.0, 43.1, 28.2, 25.8. HRMS (ESI) calcd. for C.sub.18H.sub.24NO.sub.5 [M-H].sup.−: 334.1660, Found: 334.1664. HPLC conditions: Daicel OJ-3, volume of injection: 2 μL (c=1 mg/mL), Hexane/IPA=95/5, 1.0 mL/Min, 208 nm, t.sub.R (major)=15.1 Min, t.sub.R (minor)=17.9 Min.

Example 9

Synthesis of (3R,4R)-1-(t-butoxycarbonyl)-4-o-fluorophenyl-3-carboxylic acid 3g

[0043] Under a N.sub.2 atmosphere, 2g (0.1 mmol), the catalyst Ru(1a)OAc.sub.2 (0.8 mg, 0.001 mmol), and methanol (1 mL) were added to a hydrogenation flask. After 24 h under a hydrogen atmosphere of 60 atm, the raw material was completely converted into a product. 30.4 mg, yield of product=94%, 97% ee, [a].sup.25.sub.D=+16.9 (c=0.5, CHCl3), yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.29-7.23 (m, 1H, Ar), 7.19 (tdd, J=7.3, 5.4, 1.6 Hz, 1H, Ar), 7.08-6.97 (m, 2H, Ar), 4.50 (d, J=14.1 Hz, 1H, CH.sub.2), 4.33 (d, J=11.3 Hz, 1H, CH.sub.2), 3.29 (dt, J=12.7, 3.9 Hz, 1H, CH.sub.2), 3.15 (d, J=12.9 Hz, 1H, CH), 2.96 (s, 1H, CH.sub.2), 2.87 (t, J=11.8 Hz, 1H, CH.sub.2), 2.62 (tt, J=12.6, 6.4 Hz, 1H, CH), 1.59 (dd, J=13.0, 2.6 Hz, 1H, CH.sub.2), 1.41 (s, 9H, CH.sub.3). .sup.13C NMR (101 MHz, CDCl.sub.3) δ 176.0, 160.7 (d, J=243.4 Hz), 154.7, 128.9 (d, J=13.7 Hz), 128.7 (d, J=3.7 Hz), 128.2 (d, J=8.6 Hz), 124.0 (d, J=3.6 Hz), 115.0 (d, J=22.4 Hz), 79.9, 46.3, 44.1, 43.3, 36.0, 36.0, 28.3, 24.7. .sup.19F NMR (376 MHz, CDCl.sub.3) δ −119.0. HRMS (ESI) calcd. for C.sub.17H.sub.21FNO.sub.4 [M-H].sup.−: 322.1460, Found: 322.1463. HPLC conditions: Daicel AD-3, volume of injection: 2 μL (c=1 mg/mL), Hexane/IPA=97/3, 1.0 mL/Min, 208 nm, t.sub.R (major)=15.2 Min, t.sub.R (minor)=20.8 Min.

Example 10

Synthesis of (3R,4R)-1-(t-butoxycarbonyl)-4-o-methoxyphenyl-3-carboxylic acid 3h

[0044] Under a N.sub.2 atmosphere, 2h (0.1 mmol), the catalyst Ru(1a)OAc.sub.2 (0.8 mg, 0.001 mmol), and methanol (1 mL) were added to a hydrogenation flask. After 24 h under a hydrogen atmosphere of 60 atm, the raw material was completely converted into a product. 31.8 mg, yield of product=95%, >99% ee,[a].sup.25.sub.D=+84.8 (c=0.5, CHCl3), white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.29-7.23 (m, 1H), 7.19 (tdd, J=7.3, 5.4, 1.6 Hz, 1H), 7.08-6.97 (m, 2H), 4.50 (d, J=14.1 Hz, 1H), 4.33 (d, J=11.3 Hz, 1H), 3.74 (s, 3H, CH.sub.3), 3.29 (dt, J=12.7, 3.9 Hz, 1H), 3.15 (d, J=12.9 Hz, 1H), 2.96 (s, 1H), 2.87 (t, J=11.8 Hz, 1H), 2.62 (tt, J=12.6, 6.4 Hz, 1H), 1.59 (dd, J=13.0, 2.6 Hz, 1H), 1.41 (s, 9H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ 176.0, 161.9, 159.5, 154.7, 129.0, 128.9, 128.7, 128.7, 128.2, 128.1, 124.0, 124.0, 115.1, 114.8, 79.9, 46.3, 44.1, 43.3, 36.0, 36.0, 28.3, 24.7. HRMS (ESI) calcd. for C.sub.18H.sub.24NO.sub.5[M-H].sup.−: 334.1660, Found: 334.1664. HPLC conditions: Daicel AD-3, volume of injection: 2 μL (c=1 mg/mL), Hexane/IPA=97/3, 1.0 mL/Min, 220 nm, t.sub.R (major)=23.4 Min, t.sub.R (minor)=24.9 Min.

Example 11

Synthesis of (3R,4R)-4-methyl-1-tosylpiperidin-3-carboxylic acid 3i

[0045] Under a N.sub.2 atmosphere, 2i (0.1 mmol), the catalyst Ru(1a)OAc.sub.2 (0.8 mg, 0.001 mmol), and methanol (1 mL) were added to a hydrogenation flask. After 24 h under a hydrogen atmosphere of 60 atm, the raw material was completely converted into a product. 29.1 mg, yield of product=98%, 98% ee, [a].sup.25.sub.D=+23.3 (c=0.5, CHCl3), white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.66 (d, J=8.2 Hz, 2H, Ar), 7.34 (d, J=8.0 Hz, 2H, Ar), 3.49 (dd, J=11.4, 2.3 Hz, 1H, CH.sub.2), 3.35-3.26 (m, 1H, CH.sub.2), 2.83 (ddd, J=15.5, 13.6, 6.9 Hz, 2H, CH), 2.72 (td, J=11.4, 3.0 Hz, 1H, CH), 2.44 (s, 3H, CH.sub.3), 1.84 (qd, J=9.0, 4.3 Hz, 1H, CH.sub.2), 1.74-1.65 (m, 1H, CH.sub.2), 0.86 (d, J=7.1 Hz, 3H, CH.sub.3). .sup.13C NMR (101 MHz, CDCl.sub.3) δ 177.2, 143.6, 133.1, 129.7, 127.6, 44.4, 43.2, 42.1, 30.4, 28.6, 21.5, 13.9. HRMS (ESI) calcd. for C.sub.14H.sub.18NO.sub.4S [M-H].sup.−: 296.0962, Found: 296.0963. HPLC conditions: Daicel OJ-3, volume of injection: 2 μL (c=1 mg/mL), Hexane/IPA=95/5, 1.0 mi/Min, 208 nm, t.sub.R (major)=41.0 Min, t.sub.R (minor)=43.9 Min.

Example 12

Synthesis of (3R)-1-(t-butoxycarbonyl)piperidin-3-carboxylic acid 3j

[0046] Under a N.sub.2 atmosphere, 2j (0.1 mmol), the catalyst Ru(1a)OAc.sub.2 (0.8 mg, 0.001 mmol), and methanol (1 mL) were added to a hydrogenation flask. After 24 h under a hydrogen atmosphere of 60 atm, the raw material was completely converted into a product. 22.0 mg, yield of product=96%, 96% ee, [a].sup.25.sub.D=−43.2 (c=0.5, CHCl3), white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.10 (s, 1H), 3.95-3.83 (m, 1H), 3.04 (s, 1H), 2.92-2.78 (m, 1H), 2.55-2.41 (m, 1H), 2.07 (dd, J=12.6, 3.6 Hz, 1H), 1.78-1.57 (m, 2H), 1.46 (s, 10H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ 178.9, 154.7, 79.9, 45.4, 43.6, 41.1, 28.3, 27.1, 24.1. HPLC conditions: Daicel AD-3, volume of injection: 2 μL (c=1 mg/mL), Hexane/IPA=97/3, 1.0 mL/Min, 210 nm, t.sub.R (major)=13.3 Min, t.sub.R (minor)=13.9 Min.

Example 13

Synthesis of (1S,2R)-2-p-methoxyphenylcyclohexan-1-carboxylic acid 3k

[0047] Under a N.sub.2 atmosphere, 2k (0.1 mmol), the catalyst Ru(1a)OAc.sub.2 (0.8 mg, 0.001 mmol), and methanol (1 mL) were added to a hydrogenation flask. After 24 h under a hydrogen atmosphere of 60 atm, the raw material was completely converted into a product. 22.0 mg, yield of product=96%, 96% ee, [a].sup.25.sub.D=−43.2 (c=0.5, CHCl.sub.3), white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.10 (s, 1H), 3.95-3.83 (m, 1H), 3.04 (s, 1H), 2.92-2.78 (m, 1H), 2.55-2.41 (m, 1H), 2.07 (dd, J=12.6, 3.6 Hz, 1H), 1.78-1.57 (m, 2H), 1.46 (s, 10H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ 178.9, 154.7, 79.9, 45.4, 43.6, 41.1, 28.3, 27.1, 24.1. HPLC conditions: Daicel AD-3, volume of injection: 2 μL (c=1 mg/mL), Hexane/IPA=97/3, 1.0 mL/Min, 208 nm, t.sub.R (major)=17.5 Min, t.sub.R (minor)=19.6 Min.

Example 14

Synthesis of (S)-2-phenoxybutyric acid 5a

[0048] Under a N.sub.2 atmosphere, 4a (0.1 mmol), the catalyst Ru(1a)OAc.sub.2 (0.8 mg, 0.001 mmol), and methanol (1 mL) were added to a hydrogenation flask. After 24 h under a hydrogen atmosphere of 60 atm, the raw material was completely converted into a product. 22.0 mg, yield of product=96%, 96% ee, [a].sup.25.sub.D=−43.2 (c=0.5, CHCl.sub.3), white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.10 (s, 1H), 3.95-3.83 (m, 1H), 3.04 (s, 1H), 2.92-2.78 (m, 1H), 2.55-2.41 (m, 1H), 2.07 (dd, J=12.6, 3.6 Hz, 1H), 1.78-1.57 (m, 2H), 1.46 (s, 10H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ 178.9, 154.7, 79.9, 45.4, 43.6, 41.1, 28.3, 27.1, 24.1. HPLC conditions: Daicel AD-3, volume of injection: 2 μL (c=1 mg/mL), Hexane/IPA=97/3, 1.0 mL/Min, 220 nm, t.sub.R (minor)=12.1 Min, t.sub.R (major)=13.9 Min.

Example 15

[0049] Hydrogenation of Sacubitril intermediate 6:

[0050] Under a N.sub.2 atmosphere, 6 (1 mmol) and the catalyst Ru(1a)OAc.sub.2 (0.16 mg, 0.0002 mmol) were added to two hydrogenation flasks respectively, and finally 5 mL of dichloroethane or trifluoroethanol was separately added. After 24 h under a hydrogen atmosphere, the raw material was completely converted into a product. The diastereomer ratio of Compound 7 is 98/2, and the diastereomer ratio of Compound 8 is >99/1, as determined by HPLC. HPLC conditions: Daicel AS-3, volume of injection: 2 μL (c=1 mg/mL), Hexane/IPA=92/8, 1.0 mL/Min, 220 nm, t.sub.R (7)=8.253 Min, t.sub.R (8)=10.281 Min.

[0051] It is to be understood that these examples are merely illustrative of the present invention and are not intended to limit the scope of the present invention. In addition, it should also be understood that after reading the disclosure of the present invention, various changes, modifications, and/or variations can be made to the present invention by those skilled in the art, and all these equivalents also fall within the scope of protection as defined by the appended claims of the present application.

[0052] It can be known from common technical knowledge that the present invention can be implemented by other embodiments without departing from the spirit or essential characteristics thereof. Therefore, the embodiments disclosed above are merely illustrative, and not exhaustive.

[0053] All changes within the scope of the present invention or within the equivalent scope to the present invention are included in the present invention.