CHIRAL MULTIDENTATE LIGAND, AND APPLICATION THEREOF IN ASYMMETRIC HYDROGENATION

Abstract

Disclosed are a chiral multidentate ligand (I), a preparation, and an application thereof. In this method, compound (M1) is subjected to condensation with compound (M2) followed by amine deprotection in the presence of a deprotection reagent to obtain compound (M4). Compound (1) is subjected to deprotonation by butyl lithium and phosphorization followed by dimethylamino group substitution to produce compound (3). The compound (3) and the compound (M4) are reacted in the presence of triethylamine to produce chiral multidentate ligands.

##STR00001##

Claims

1. A chiral multidentate ligand of formula (I) ##STR00064## wherein R.sub.1 and R.sub.2 each are independently an alkyl group or an aryl group; R.sub.3 and R.sub.4 each are independently an alkyl group, an aryl group, or hydrogen; R.sub.5 and R.sub.6 each are independently an alkyl group or an aryl group; and R.sub.5 and R.sub.6 form a ring or not.

2. The chiral multidentate ligand of claim 1, wherein the chiral multidentate ligand is selected from the group consisting of L1-L10, shown as: ##STR00065##

3. A method of preparing the chiral multidentate ligand of claim 1, comprising: (S1) subjecting compound (M1) containing an amino-protecting group and compound (M2) to undergo a condensation reaction to obtain compound (M3); and subjecting the compound (M3) to amine deprotection in the presence of a deprotection reagent to obtain compound (M4); wherein when the amino-protecting group is a t-butyloxy carbonyl (Boc) group, the deprotection reagent is selected from the group consisting of trifluoroacetic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid, and phosphoric acid; and when the amino-protecting group is a benzyloxycarbonyl (Cbz) group, the amino-protecting group is removed under the catalysis of Pd/C catalysts or Pd (OH).sub.2/C catalyst in a hydrogen atmosphere; (S2) subjecting compound (1) to deprotonation by butyl lithium and phosphorization to produce compound (2); and substituting a dimethylamino group in the compound (2) with an acetoxy group to obtain compound (3); and (S3) reacting the compound (3) with the compound (M4) in the presence of triethylamine to produce chiral multidentate ligands L1-L9, wherein an enantiomer L10 of a chiral multidentate ligand L3 is synthesized from corresponding chiral raw materials through a method of preparing the chiral multidentate ligand L3, as shown in the following reaction scheme: ##STR00066## ##STR00067##

4. The method of claim 3, wherein the deprotection reagent is trifluoroacetic acid or hydrochloric acid.

5. A catalyst, comprising: the chiral multidentate ligand of claim 1; and a precursor containing a transition metal; wherein the transition metal is selected from the group consisting of ruthenium, rhodium, iridium, ferrum, cobalt, nickel, manganese, and copper.

6. The catalyst of claim 5, wherein the precursor is selected from the group consisting of [Ir(NBD)Cl].sub.2, [Ir(NBD).sub.2]X, [Ir(COD)Cl].sub.2, [Ir(COD).sub.2]X, [Rh(NBD).sub.2]X, [Rh(NBD)Cl].sub.2, Rh(acac)(CO).sub.2, [Rh(COD)Cl].sub.2, Rh(ethylene).sub.2(acac), [Rh(ethylene).sub.2C.sub.1]2, [Rh(COD).sub.2]X, RhCl(PPh.sub.3).sub.3, Ru(aryl group)X.sub.2, RuX.sub.2(L).sub.2(diphosphine), Ru(arene)X.sub.2(diphosphine), Ru(methallyl).sub.2(diphosphine), Ru(aryl group)X.sub.2(PPh.sub.3), RuX.sub.2(cymene), RuCl.sub.2(COD), (Ru(COD).sub.2)X, RuX.sub.2(diphosphine), Ru(ArH)C.sub.12, Ru(COD)(methallyl).sub.2, (Ni(allyl)X).sub.2, Ni(acac).sub.2, Ni(COD).sub.2, NiX.sub.2, MnX.sub.2, Mn(acac).sub.2, CoX.sub.2, FeX.sub.2, CuX, CuX.sub.2, AgX, [Pd(allyl)Cl].sub.2; PdCl.sub.2, Pd(OAc).sub.2, and Pd(CF.sub.3COO).sub.2; wherein in the precursor, R is an alkyl group, an alkoxy group, or a substituted alkyl group; X is selected from the group consisting of Cl.sup.−, Br.sup.−, I.sup.−, BF.sub.4.sup.−, C.sub.104.sup.−, SbF.sub.6.sup.−, PF.sub.6.sup.−, TfO.sup.−, RCOO.sup.−, and B(Ar).sub.4.sup.−; Ar is 3,5-difluoromethyl benzene or fluorobenzene; and L is CH.sub.3CN or N,N-Dimethylformamide (DMF).

7. A method for preparing a chiral alcohol through an asymmetric hydrogenation reaction, comprising: applying the catalyst of claim 5 to the asymmetric hydrogenation reaction.

8. The method of claim 7, further comprising: reacting the precursor and the chiral multidentate ligand in a first solvent to obtain the catalyst; mixing the catalyst and a substrate in a second solvent followed by addition of a base to obtain a reaction mixture; transferring the reaction mixture to a stainless-steel autoclave; and subjecting the reaction mixture to hydrogen substitution three times followed by the asymmetric hydrogenation reaction at a temperature in the presence of hydrogen gas, slow release of the hydrogen gas, filtration, and rotary evaporation to produce the chiral alcohol; wherein the first solvent and the second solvent are independently selected from the group consisting of isopropanol, ethanol, toluene, n-hexane, dichloromethane, tetrahydrofuran, methyl tert-butyl ether, and a combination thereof; the base is potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, or a combination thereof; and the asymmetric hydrogenation reaction is performed at 20-80° C. and 10-80 atm.

9. The method of claim 7, wherein the catalyst is applied to hydrogenation of α-aminoketone, as shown in the following reaction scheme: ##STR00068## wherein R.sup.1 and R.sup.2 each are independently hydrogen, an alkyl group, an aryl group or a nitrogen protecting group.

10. The method of claim 7, wherein the catalyst is applied to asymmetric hydrogenation of α-hydrochlorinated ketone, as shown in the following reaction scheme: ##STR00069##

11. The method of claim 7, wherein the catalyst is applied to synthesis of phenylephrine, mirabelon, ticagrelor, or benazepril.

12. A compound of formula (M4-3): ##STR00070## wherein*represents that the compound (M4-3) comprises R and S configurations.

13. A compound of formula (M3-3): ##STR00071## wherein P is Cbz or Boc; and*represents that the compound (M3-3) comprises R and S configurations.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0049] FIG. 1 is a nuclear magnetic resonance (NMR) hydrogen spectrum of compound M3-3 according to an embodiment of the present disclosure, where R is ′Bu, and P is benzyloxycarbonyl (Cbz);

[0050] FIG. 2 is an NMR hydrogen spectrum of compound M3-3 according to an embodiment of the present disclosure, where R is .sup.tBu, and P is t-butyloxy carbonyl (Boc);

[0051] FIG. 3 is an NMR hydrogen spectrum of compound M4-3 according to an embodiment of the present disclosure, where R is .sup.tBu;

[0052] FIG. 4 is an NMR hydrogen spectrum of a chiral multidentate ligand L1 according to an embodiment of the present disclosure;

[0053] FIG. 5 is an NMR hydrogen spectrum of a chiral multidentate ligand L2 according to an embodiment of the present disclosure;

[0054] FIG. 6 is an NMR hydrogen spectrum of a chiral multidentate ligand L3 according to an embodiment of the present disclosure;

[0055] FIG. 7 is an NMR hydrogen spectrum of a chiral multidentate ligand L4 according to an embodiment of the present disclosure;

[0056] FIG. 8 is an NMR hydrogen spectrum of a chiral multidentate ligand L5 according to an embodiment of the present disclosure;

[0057] FIG. 9 is an NMR hydrogen spectrum of a chiral multidentate ligand L6 according to an embodiment of the present disclosure;

[0058] FIG. 10 is an NMR hydrogen spectrum of a chiral multidentate ligand L7 according to an embodiment of the present disclosure;

[0059] FIG. 11 is an NMR hydrogen spectrum of a chiral multidentate ligand L8 according to an embodiment of the present disclosure; and

[0060] FIG. 12 is an NMR hydrogen spectrum of a chiral multidentate ligand L9 according to an embodiment of the present disclosure.

DETAILED DESCRIPTION OF EMBODIMENTS

[0061] This application will be described in detail below with reference to the embodiments, but these embodiments are not intended to limit the scope of this application.

Example 1 Preparation of an Intermediate Compound (S.SUB.C., R.SUB.P.)-2

[0062] ##STR00012##

[0063] A solution of compound (S)-1 (15 g, 58 mmol, 1.0 equiv.) in anhydrous ethyl ether (145 mL) was added dropwise with a solution of BuLi (30 mL) in hexane (2.3 mol/L, 1.2 equiv.) under stirring in the presence of N.sub.2 at 0° C., naturally restored to the room temperature and stirred for 4.0 h. The reaction mixture was added dropwise with Ar.sub.2PCl (70 mmol, 1.2 equiv.) under reflux and continued to reflux for about 4 h. After the reaction was confirmed by thin-layer chromatography (TLC) to be completed, the reaction mixture was added with water for quenching and extracted with ether to obtain an organic phase. The organic phase was dried with anhydrous sodium sulfate, filtered, and evaporated to obtain a red oily liquid. After that, the red oily liquid was beaten with a certain amount of ethyl ether to obtain an orange-yellow solid product as the compound (S.sub.C, R.sub.P)-2 (65%-83% yield).

Example 2 Preparation of an Intermediate Compound (S.SUB.C., R.SUB.P.)-3

[0064] ##STR00013##

[0065] A mixture of compound (S.sub.C, R.sub.P)-2 (30 mmol) and acetic anhydride (24 mL) was heated under protection of nitrogen at 100° C. for about 1.0 h. After the reaction was confirmed by TLC to be completed, the reaction mixture was evaporated under reduced pressure to obtain an orange solid as the compound (S.sub.C, R.sub.P)-3 with a yield of more than 95%. Then the compound (S.sub.C, R.sub.P)-3 was directly used in the next procedures without purification.

Example 3 Preparation of an Intermediate Compound M3

[0066] ##STR00014##

[0067] N-protecting group-containing glycine (M1) (1.2 eq) and chiral amino alcohol (M2) (1.0 eq) were dissolved in dichloromethane and subjected to a condensation reaction in the presence of a condensation agent dicyclohexylcarbodiimide (DCC) (1.5 eq). After the reaction was confirmed by TLC to be completed, the reaction mixture was filtered to remove a by-product (solid N,N′-dicyclohexylurea) to obtain a crude amide intermediate (M3), which was then purified by column separation to obtain a pure compound M3 (76%-88% yield). Characterization data was shown as follows:

[0068] compound M3-3 (where R is .sup.tBu, and P is benzyloxycarbonyl (Cbz)): .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.31-7.26 (m, 5H), 6.72 (d, J=9.6 Hz, 1H), 6.24 (s, 1H), 5.07 (s, 2H), 3.93 (dd, J=16.6, 6.0 Hz, 1H), 3.82-3.73 (m, 3H), 3.40 (t, J=10.3 Hz, 1H), 3.06 (br, 1H), 0.85 (s, 9H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ 170.75, 157.04, 136.10, 128.46, 128.14, 127.98, 67.05, 61.62, 59.54, 44.53, 33.45, 26.59; and

[0069] compound M3′-3 (where R is .sup.tBu, and P is t-butyloxy carbonyl (Boc)): .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.58 (d, J=9.1 Hz, 1H), 5.62 (s, 1H), 3.89-3.69 (m, 4H), 3.49 (s, 1H), 3.30 (s, 1H), 1.44 (s, 9H), 0.93 (s, 9H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ 170.98, 156.53, 80.40, 62.37, 59.72, 44.78, 33.46, 28.26, 26.74.

Example 4 Preparation of an Intermediate Compound M4

[0070] ##STR00015##

[0071] Compound M3 (where P is Boc) was dissolved in trifluoroacetic acid/dichloromethane (V:V=1:1) followed by reaction at room temperature for 4 h. After the reaction was confirmed by TLC to be completed, the reaction mixture was evaporated to remove the solvent and excess trifluoroacetic acid. The residue was neutralized with a saturated solution of sodium bicarbonate followed by extraction with dichloromethane (3 times). The organic phases were combined, dried with anhydrous sodium sulfate, and filtered to obtain a compound M4 with a crude yield of higher than 90%. The compound M4 was directly used in the next procedures without purification.

[0072] Compound M3′ (where P is Cbz) was dissolved in methanol and added with 5% Pd/C. The reaction suspension was placed in an autoclave, subjected to nitrogen substitution 3 times, hydrogen substitution 3 times, addition of 5-10 atm hydrogen, and reaction at room temperature for 12 h. After that, the hydrogen was slowly released carefully and the Pd/C was filtered out to obtain a compound M4 with a crude yield of higher than 98%. The compound M4 was directly used in the next procedures without purification. Characterization data was shown as follows:

[0073] compound M4 (where R is .sup.tBu): .sup.1HNMR (400 MHz, CDCl.sub.3) δ 7.59 (d, J=8.9 Hz, 1H), 3.85 (dd, J=11.2, 3.2 Hz, 1H), 3.76 (td, J=8.9, 3.2 Hz, 1H), 3.50 (dd, J=11.2, 8.6 Hz, 1H), 3.37 (s, 2H), 2.39 (s, 3H), 0.94 (s, 9H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ 174.07, 62.99, 59.74, 44.56, 33.35, 26.82.

Example 5 Preparation of a Chiral Multidentate Ligand L1

[0074] ##STR00016##

[0075] To a 50 mL reaction tube were added acetate 3a (0.91 g, 2.0 mmol) and compound M4-1 (0.29 g, 2.2 mmol) followed by nitrogen substitution. Then the reaction mixture was sequentially added with triethylamine (0.41 g, 4 mmol, 2 equiv) and anhydrous methanol (20 mL), followed by stirring at room temperature for 2 h, reflux overnight, evaporation, concentration, and column chromatography to obtain a pale yellow foamy solid as the chiral multidentate ligand L1(0.63 g, 61% yield).

[0076] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.53-7.49 (m, 2H), 7.37-7.35 (m, 3H), 7.24-7.18 (m, 5H), 4.42 (s, 1H), 4.29 (s, 1H), 4.16-4.09 (m, 1H), 3.96 (s, 5H), 3.85-3.76 (m, 2H), 3.51-3.43 (m, 1H), 3.41-3.34 (m, 1H), 2.86 (dd, J=16.0 Hz, 60.0 Hz, 2H), 1.37 (d, J=8.2 Hz, 3H), 1.04 (d, J=4.3 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ 173.61, 140.10 (d, J=9.2 Hz), 136.88 (d, J=9.2 Hz), 134.96, 134.81, 132.51 (d, J=18.5 Hz), 129.31, 128.48 (d, J=2.0 Hz), 128.49, 128.28 (d, J=8.2 Hz), 96.53, 96.29, 75.23 (d,J=8.2 Hz), 71.73 (d,J=4.3 Hz), 69.77, 69.58 (d,J=4.3 Hz), 69.24, 67.62, 51.73 (d, J=8.2 Hz), 48.62, 48.08, 19.00, 16.80; .sup.31P NMR (101 MHz, CDCl.sub.3) δ −24.85.

Example 6 Preparation of a Chiral Multidentate Ligand L2

[0077] ##STR00017##

[0078] To a 50 mL reaction tube were added acetate 3a (0.91 g, 2.0 mmol) and compound M4-2 (0.35 g, 2.2 mmol) followed by nitrogen substitution. Then the reaction mixture was sequentially added with triethylamine (0.41 g, 4 mmol, 2 equiv) and anhydrous methanol (20 mL), followed by stirring at room temperature for 2 h, reflux overnight, evaporation, concentration, and column chromatography to obtain a pale yellow foamy solid as the chiral multidentate ligand L2 (0.61 g, 55% yield).

[0079] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.54-7.50 (m, 2H), 7.44-7.37 (m, 4H), 7.27-7.20 (m, 4H), 4.43 (s, 1H), 4.30 (s, 1H), 4.20-4.16 (m, 1H), 3.98 (s, 5H), 3.83 (s, 1H), 3.63-3.58 (m, 1H), 3.53-3.41 (m, 2H), 2.87 (dd, J=17.0 Hz, 66.7 Hz, 2H), 1.88-1.76 (m, 1H), 1.43 (d, J=8.2 Hz, 3H), 0.92 (d, J=8.2 Hz, 3H), 0.88 (d, J=8.2 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ 173.89, 140.13 (d, J=10.4 Hz), 136.99 (d, J=8.5 Hz), 135.01, 134.81, 132.52 (d, J=18.1 Hz), 129.32, 128.51 (d, J=1.9 Hz), 128.19 (d, J=7.1 Hz), 96.58, 96.28, 75.21 (d, J=8.2 Hz), 71.72 (d, J=4.2 Hz), 69.76, 69.60, 69.49, 69.20, 64.61, 57.79, 51.64 (d, J=8.2 Hz), 48.39, 28.77, 19.59, 19.12, 19.05; .sup.31P NMR (101 Hz, CDCl.sub.3) δ-24.73.

Example 7 Preparation of a Chiral Multidentate Ligand L3

[0080] ##STR00018##

[0081] To a 50 mL reaction tube were added acetate 3a (0.91 g, 2.0 mmol) and compound M4-3 (0.38 g, 2.2 mmol) followed by nitrogen substitution. Then the reaction mixture was sequentially added with triethylamine (0.41 g, 4 mmol, 2 equiv) and anhydrous methanol (20 mL), followed by stirring at room temperature for 2 h, reflux overnight, evaporation, concentration, and column chromatography to obtain a pale yellow foamy solid as the chiral multidentate ligand L3 (0.58 g, 51% yield).

[0082] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.50-7.47 (m, 3H), 7.25-7.21 (m, 3H), 7.21-7.13 (m, 4H), 4.41 (s, 1H), 4.30 (s, 1H), 4.20-4.18 (m, 1H), 3.99 (s, 5H), 3.80-3.74 (m, 2H), 3.62-3.60 (m, 1H), 3.40-3.35 (m, 1H), 2.82 (dd, J=17.5 Hz, 117.2 Hz, 2H), 1.38 (d, J=6.7 Hz, 3H), 0.89 (s, 9H);

[0083] .sup.13C NMR (101 MHz, CDCl.sub.3) δ 174.09, 139.70 (d, J=9.7 Hz), 136.74 (d, J=8.6 Hz), 134.81, 134.67, 132.54 (d, J=19.1 Hz), 129.20, 128.66, 128.50 (d, J=6.3 Hz), 128.18 (d, J=7.7 Hz), 96.28 (d, J=23.7 Hz), 75.18 (d, J=7.6 Hz), 71.57 (d, J=4.2 Hz), 69.70, 69.59, 69.56, 69.14, 63.78, 60.30, 51.43 (d, J=8.5 Hz), 48.06, 33.32, 26.94, 19.18;

[0084] .sup.31P NMR (101 MHz, CDCl.sub.3) δ-25.04.

[0085] FIGS. 1-4 are NMR hydrogen spectra of compound M3-3 (where R is .sup.tBu, and P is Cbz), compound M3-3 (where R is .sup.tBu, and P is Boc), compound M4-3 (where R is tBu), and a chiral multidentate ligand L1, respectively.

Example 8 Preparation of a Chiral Multidentate Ligand L4

[0086] ##STR00019##

[0087] To a 50 mL reaction tube were added acetate 3a (0.91 g, 2.0 mmol) and compound M4-4 (0.46 g, 2.2 mmol) followed by nitrogen substitution. Then the reaction mixture was sequentially added with triethylamine (0.41 g, 4 mmol, 2 equiv) and anhydrous methanol (20 mL), followed by stirring at room temperature for 2 h, reflux overnight, evaporation, concentration, and column chromatography to obtain a pale yellow foamy solid as the chiral multidentate ligand L4 (0.74 g, 61% yield).

[0088] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.55-7.51 (m, 2H), 7.43-7.29 (m, 4H), 7.30-7.16 (m, 9H), 4.40 (s, 1H), 4.32 (s, 1H), 4.13-4.05 (m, 1H), 3.98 (s, 5H), 3.95-3.82 (m, 1H), 3.81 (s, 1H), 3.59-3.53 (m, 1H), 3.48-3.41 (m, 1H), 2.90-2.67 (m, 4H), 1.19 (d, J=8.0 Hz, 3H);

[0089] .sup.13C NMR (101 MHz, CDCl.sub.3) δ 173.63, 140.14 (d, J=9.6 Hz), 137.88, 136.99 (d, J=8.2 Hz), 134.98, 134.78, 132.45 (d, J=18.1 Hz), 129.28, 129.24, 128.57, 128.49, 128.42, 128.20 (d, J=8.2 Hz), 126.60, 96.50 (d, J=24.0 Hz), 75.10 (d, J=7.7 Hz), 71.69 (d, J=4.3 Hz), 69.69, 69.52, 69.43, 69.19, 65.05, 53.58, 51.45 (d, J=8.5 Hz), 48.29, 36.80, 18.73;

[0090] .sup.31P NMR (101 MHz, CDCl.sub.3) δ−24.93.

Example 9 Preparation of a Chiral Multidentate Ligand L5

[0091] ##STR00020##

[0092] To a 50 mL reaction tube were added acetate 3a (0.91 g, 2.0 mmol) and compound M4-5 (0.43 g, 2.2 mmol) followed by nitrogen substitution. Then the reaction mixture was sequentially added with triethylamine (0.41 g, 4 mmol, 2 equiv) and anhydrous methanol (20 mL), followed by stirring at room temperature for 2 h, reflux overnight, evaporation, concentration, and column chromatography to obtain a pale yellow foamy solid as the chiral multidentate ligand L5 (0.68 g, 58% yield).

[0093] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.93-7.88 (m, 1H), 7.54-7.49 (m, 2H), 7.41-7.32 (m, 5H), 7.33-7.27 (m, 1H), 7.26-7.23 (m, 6H), 4.97-4.84 (m, 1H), 4.40 (s, 1H), 4.32 (d, J=4.3 Hz, 1H), 4.23-4.10 (m, 1H), 4.02 (s, 5H), 3.78 (s, 1H), 3.73 (d, J=8.7 Hz, 2H), 2.92 (dd, J=18.1 Hz, 56.0 Hz, 2H), 1.34 (d, J=4.0 Hz, 3H);

[0094] .sup.13C NMR (101 MHz, CDCl.sub.3) δ 173.40, 139.89 (d, J=9.5 Hz), 138.93, 136.82 (d, J=9.5 Hz), 134.89, 134.75, 132.50 (d, J=18.1 Hz), 129.30, 128.78, 128.61 (d, J=7.5 Hz), 128.50, 128.19 (d, J=8.0 Hz), 127.80, 126.91, 96.32 (d, J=23.5 Hz), 75.21 (d, J=7.7 Hz), 71.71 (d, J=4.0 Hz), 69.79, 69.72, 69.59, 69.23, 67.03, 56.28, 51.65 (d, J=8.0 Hz), 48.51, 18.98;

[0095] .sup.31P NMR (101 MHz, CDCl.sub.3) δ−24.95.

Example 10 Preparation of a Chiral Multidentate Ligand L6

[0096] ##STR00021##

[0097] To a 50 mL reaction tube were added acetate 3b (0.97 g, 2.0 mmol) and compound M4-3 (0.38 g, 2.2 mmol) followed by nitrogen substitution. Then the reaction mixture was sequentially added with triethylamine (0.41 g, 2 equiv) and anhydrous methanol (20 mL), followed by stirring at room temperature for 2 h, reflux overnight, evaporation, concentration, and column chromatography to obtain a pale yellow foamy solid as the chiral multidentate ligand L6 (0.68 g, 57% yield).

[0098] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.60-7.54 (m, 1H), 7.41 (t, J=8.5 Hz, 2H), 7.20 (d, J=7.9 Hz, 2H), 7.15-7.04 (m, 4H), 4.38 (s, 1H), 4.28 (t, J=2.4 Hz, 1H), 4.30-4.18 (m, 1H), 4.00 (s, 5H), 3.82-3.78 (m, 2H), 3.66-3.58 (m, 1H), 3.46-3.39 (m, 1H), 2.82 (dd, J=18.0 Hz, 80.2 Hz, 2H), 2.39 (s, 3H), 2.30 (s, 3H), 1.40 (d, J=4.3 Hz, 3 H), 0.89 (s, 9 H);

[0099] .sup.13C NMR (101 MHz, CDCl.sub.3) δ 173.88, 139.23, 138.60, 136.26 (d, J=8.5 Hz), 134.85, 134.62, 133.40 (d, J=8.5 Hz), 132.51 (d, J=19.2 Hz), 129.42, 129.34, 129.08 (d, J=8.5 Hz), 95.80 (d, J=23.4 Hz), 75.81 (d, J=8.0 Hz), 71.71, 69.78, 69.62, 69.56, 69.14, 63.61, 60.35, 51.55 (d, J=9.7 Hz), 47.93, 33.40, 27.00, 21.42, 21.35, 19.23;

[0100] .sup.31P NMR (101 MHz, CDCl.sub.3) δ-27.50.

Example 11 Preparation of a Chiral Multidentate Ligand L7

[0101] ##STR00022##

[0102] To a 50 mL reaction tube were added acetate 3c (1.02 g, 2.0 mmol) and compound M4-3 (0.38 g, 2.2 mmol) followed by nitrogen substitution. Then the reaction mixture was sequentially added with triethylamine (0.17 mL, 1.2 mmol, 3 equiv) and anhydrous methanol (20 mL), followed by stirring at room temperature for 2 h, reflux overnight, evaporation, concentration, and column chromatography to obtain a pale yellow foamy solid as the chiral multidentate ligand L7 (0.66 g, 53% yield).

[0103] .sup.1H NMR (600 MHz, CDCl.sub.3) δ 7.50 (d, J=8.3 Hz, 1H), 7.14 (d, J=8.4 Hz, 2H), 7.02 (s, 1H), 6.89 (s, 1H), 6.83 (d, J=7.6 Hz, 2H), 4.40 (s, 1H), 4.30 (s, 1H), 4.21 (tt, J=6.5, 3.3 Hz, 1H), 4.02 (s, 5H), 3.81 (s, 1H), 3.78 (d, J=2.7 Hz, 1H), 3.62 (td, J=8.4, 2.7 Hz, 1H), 3.42 (dd, J=11.1, 8.5 Hz, 1H), 2.92 (d, J=17.5 Hz, 1H), 2.68 (d, J=17.5 Hz, 1H), 2.32 (s, 6H), 2.21 (s, 6H), 1.40 (d, J=6.7 Hz, 3H), 0.91 (s, 9 H).

[0104] .sup.13C NMR (151 MHz, CDCl.sub.3) δ 174.21, 139.16 (d, J=8.9 Hz), 137.92 (d, J=6.8 Hz), 137.49 (d, J=8.0 Hz), 136.31 (d, J=7.9 Hz), 132.33 (d, J=20.4 Hz), 130.84, 130.56, 130.38 (d, J=19.5 Hz), 95.80 (d, J=22.9 Hz), 75.83 (d, J=7.8 Hz), 71.67 (d, J=4.0 Hz), 69.69, 69.37 (d, J=3.5 Hz), 68.83, 63.82, 60.46, 51.23 (d, J=8.8 Hz), 47.67, 33.29, 26.89, 21.31 (d, J=13.0 Hz), 18.93.

[0105] .sup.31P NMR (243 MHz, CDCl.sub.3) δ−25.07.

Example 12 Preparation of a Chiral Multidentate Ligand L8

[0106] ##STR00023##

[0107] To a 50 mL reaction tube were added acetate 3 d (1.36 g, 2.0 mmol) and compound M4-3 (0.38 g, 2.2 mmol) followed by nitrogen substitution. Then the reaction mixture was sequentially added with triethylamine (0.41 g, 4 mmol, 2 equiv) and anhydrous methanol (20 mL), followed by stirring at room temperature for 2 h, reflux overnight, evaporation, concentration, and column chromatography to obtain a pale yellow foamy solid as the chiral multidentate ligand L8 (0.75 g, 47% yield).

[0108] .sup.1H NMR (600 MHz, CDCl.sub.3) δ 7.72 (d, J=8.1 Hz, 1H), 7.42 (s, 1H), 7.40 (dd, J=8.6, 1.6 Hz, 2H), 7.32 (s, 1H), 7.21 (dd, J=8.1, 1.6 Hz, 2H), 4.37 (s, 1H), 4.27 (t, J=2.2 Hz, 1H), 4.13 (dd, J=6.6, 2.6 Hz, 1H), 4.06 (s, 5H), 3.80 (dd, J=11.1, 2.7 Hz, 1H), 3.72 (s, 1H), 3.59 (td, J=8.3, 2.6 Hz, 1H), 3.43 (dd, J=11.0, 8.4 Hz, 1H), 2.71 (d, J=17.7 Hz, 1H), 2.55 (d, J=17.7 Hz, 1H), 1.67 (br, 3H), 1.35 (d, J=6.6 Hz, 3H), 1.30 (s, 18H), 1.22 (s, 18H), 0.90 (s, 9H).

[0109] .sup.13C NMR (151 MHz, CDCl.sub.3) δ 174.44, 150.79 (d, J=6.7 Hz), 150.26 (d, J=7.2 Hz), 138.14 (d, J=7.9 Hz), 135.01 (d, J=7.5 Hz), 128.80 (d, J=20.9 Hz), 127.65 (d, J=20.7 Hz), 122.99, 122.73, 95.47 (d, J=21.7 Hz), 77.39 (d, J=6.8 Hz), 71.23 (d, J=3.8 Hz), 69.65, 69.08 (d, J=3.7 Hz), 68.58, 64.17, 60.61, 51.96 (d, J=8.9 Hz), 48.65, 34.88 (d, J=9.8 Hz), 33.22, 31.41 (d, J=14.6 Hz), 26.89, 19.03.

[0110] .sup.31P NMR (243 MHz, CDCl.sub.3) δ−23.86.

Example 13 Preparation of a Chiral Multidentate Ligand L9

[0111] ##STR00024##

[0112] To a 50 mL reaction tube were added acetate 3 e (1.48 g, 2.0 mmol) and compound M4-3 (0.38 g, 2.2 mmol) followed by nitrogen substitution. Then the reaction mixture was sequentially added with triethylamine (0.41 g, 4 mmol, 2 equiv) and anhydrous methanol (20 mL), followed by stirring at room temperature for 2 h, reflux overnight, evaporation, concentration, and column chromatography to obtain a pale yellow foamy solid as the chiral multidentate ligand L9 (0.77 g, 45% yield).

[0113] .sup.1H NMR (600 MHz, CDCl.sub.3) δ 7.77 (d, J=8.1 Hz, 1H), 7.39 (d, J=8.3 Hz, 2H), 7.22 (d, J=7.7 Hz, 2H), 4.37 (s, 1H), 4.28 (s, 1H), 4.14 (dd, J=6.6, 2.5 Hz, 1H), 4.05 (s, 5H), 3.81 (dd, J=11.1, 2.6 Hz, 1H), 3.71 (s, 3H), 3.69 (s, 1H), 3.60 (dd, J=8.1, 2.6 Hz, 1H), 3.58 (s, 3H), 3.44 (dd, J=11.0, 8.5 Hz, 1H), 2.76 (d, J=17.7 Hz, 1H), 2.57 (d, J=17.7 Hz, 1H), 1.67 (br, 3H), 1.40 (s, 18H), 1.35 (d, J=6.6 Hz, 3H), 1.31 (s, 18H), 0.91 (s, 9H).

[0114] .sup.13C NMR (151 MHz, CDCl.sub.3) δ 174.38, 160.51, 160.36, 143.76 (d, J=6.9 Hz), 143.19 (d, J=7.7 Hz), 132.97 (d, J=21.8 Hz), 132.63 (d, J=5.9 Hz), 131.77 (d, J=21.5 Hz), 129.57 (d, J=5.9 Hz), 95.40 (d, J=21.8 Hz), 77.76 (d, J=6.9 Hz), 71.07 (d, J=3.6 Hz), 69.59, 69.17 (d, J=3.7 Hz), 68.61, 64.36 (d, J=2.4 Hz), 64.15, 60.61, 51.91 (d, J=8.5 Hz), 48.56, 35.84 (d, J=3.3 Hz), 33.24, 32.04 (d, J=12.9 Hz), 26.89, 18.97.

[0115] .sup.31P NMR (243 MHz, CDCl.sub.3) δ-26.53.

Example 14 Preparation of a Chiral Multidentate Ligand L10

[0116] ##STR00025##

[0117] To a 50 mL reaction tube were added acetate (R.sub.C, S.sub.P)-3a (0.91 g, 2.0 mmol) and compound (R)-M4-3 (0.38 g, 2.2 mmol) followed by nitrogen substitution. Then the reaction mixture was sequentially added with triethylamine (0.41 g, 4 mmol, 2 equiv) and anhydrous methanol (20 mL), followed by stirring at room temperature for 2 h, reflux overnight, evaporation, concentration, and column chromatography to obtain a pale yellow foamy solid as the chiral multidentate ligand L10 (0.58 g, 51% yield).

[0118] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.53-7.48 (m, 3H), 7.28-7.22 (m, 3H), 7.22-7.12 (m, 4H), 4.44 (s, 1H), 4.32 (s, 1H), 4.23-4.19 (m, 1H), 4.02 (s, 5H), 3.84-3.73 (m, 2H), 3.63-3.59 (m, 1H), 3.43-3.38 (m, 1H), 2.84 (dd, J=17.5 Hz, 117.2 Hz, 2H), 1.39 (d, J=6.7 Hz, 3H), 0.90 (s, 9H);

[0119] .sup.13C NMR (101 MHz, CDCl.sub.3) δ 174.12, 139.72 (d, J=9.7 Hz), 136.77 (d, J=8.6 Hz), 134.83, 134.68, 132.58 (d, J=19.1 Hz), 129.24, 128.70, 128.54 (d, J=6.3 Hz), 128.20 (d, J=7.7 Hz), 96.29 (d, J=23.7 Hz), 75.21 (d, J=7.6 Hz), 71.59 (d, J=4.2 Hz), 69.73, 69.63, 69.59, 69.17, 63.80, 60.32, 51.48 (d, J=8.5 Hz), 48.03, 33.30, 26.96, 19.20;

[0120] .sup.31P NMR (101 MHz, CDCl.sub.3) δ−25.08.

Examples 15-24 Asymmetric Catalytic Hydrogenation of Simple Aromatic Ketones (S/C=10,000)

[0121] To a 4.0 mL reaction flask were added a catalyst precursor [Ir(COD)C.sub.1]2(1.4 mg, 2.0×10.sup.−3 mmol) and a ligand (L1-L10) (4.2×10.sup.−3 mmol) in an argon-filled glove box. The mixture was added with dried ′PrOH (2 mL) for dissolving, and stirring at 25° C. for 2.0 h until the solution was changed from yellow to orange to obtain a metal complex solution. To a 5.0 mL hydrogenation flask were added anhydrous K2CO3 (10 μL, 0.02 mmol/mL) and freshly distilled acetophenone (0.2 mmol), followed by 1.0 mL of dried ′PrOH for dissolving. Then the metal complex solution (10 μL) was injected dropwise into the hydrogenation flask by using a micro syringe. The hydrogenation flask was carefully placed into an autoclave. The autoclave was tightened, removed from the glove box, and subjected to hydrogen substitution with 10 atm H.sub.2 three times. After that, the autoclave was filled with 20 atm H.sub.2, and the inlet valve of the autoclave was closed to allow the reaction mixture to undergo asymmetric catalytic hydrogenation under stirring at room temperature for 4 h. After the reaction was completed, the outlet valve of the autoclave was opened to slowly release H.sub.2. The reaction mixture was subjected to rapid silica gel column chromatography with ethyl acetate as the rinsing agent to remove the metal complex, and evaporated to remove the solvent to obtain chiral alcohols. The chemical structures of the chiral alcohols were determined by 1H NMR and 13C NMR. The ee values of the chiral alcohols were determined by using chiral high performance liquid chromatography and chiral gas chromatography, and the spin values of the chiral alcohols were determined. The results were shown in Table 1.

TABLE-US-00001 TABLE 1 Screening of ligands for asymmetric catalytic hydrogenation of acetophenone Examples Ligands Solvents Bases conv. (%) ee (%) Example 15 L1 .sup.iPrOH .sup.tBuOK >99 >99 Example 16 L2 .sup.iPrOH .sup.tBuOK >99 >99 Example 17 L3 .sup.iPrOH .sup.tBuOK >99 >99 Example 18 L4 .sup.iPrOH .sup.tBuOK >99 97 Example 19 L5 .sup.iPrOH .sup.tBuOK >99 96 Example 20 L6 .sup.iPrOH .sup.tBuOK 85 95 Example 21 L7 .sup.iPrOH .sup.tBuOK 80 93 Example 22 L8 .sup.iPrOH .sup.tBuOK 69 94 Example 23 L9 .sup.iPrOH .sup.tBuOK 65 91 Example 24 L10 .sup.iPrOH .sup.tBuOK >99 −99 Noted: In Example 24, −99% ee indicates that the product catalyzed with L10 (ligand L10 is the enantiomeric equivalent of ligand L3 in Example 17) is of the opposite configuration to that obtained in Example 17.

Examples 25-38 Asymmetric Catalytic Hydrogenation of Aromatic Ketones

[0122] In Examples 25-38, compound L3 was used as the ligand, and the conditions of the asymmetric catalytic hydrogenation of aromatic ketones were optimized according to the above mentioned operation. Results were shown in Table 2.

TABLE-US-00002 TABLE 2 Optimization of conditions for asymmetric catalytic hydrogenation of acetophenone Examples Ligands Solvents Bases conv. (%) ee (%) Example 17 L3 .sup.iPrOH .sup.tBuOK >99 >99 Example 25 L3 MeOH .sup.tBuOK 10 98 Example 26 L3 EtOH .sup.tBuOK 80 99 Example 27 L3 EtOAc .sup.tBuOK 20 98 Example 28 L3 DCM .sup.tBuOK 95 98 Example 29 L3 THF .sup.tBuOK 92 95 Example 30 L3 Hexane .sup.tBuOK 99 >99 Example 31 L3 Toluene .sup.tBuOK 96 >99 Example 32 L3 .sup.iPrOH K.sub.2CO.sub.3 >99 >99 Example 33 L3 .sup.iPrOH Cs.sub.2CO.sub.3 >99 >99 Example 34 L3 .sup.iPrOH KOH >99 >99 Example 35 L3 .sup.iPrOH NaOH >99 >99 Example 36 L3 .sup.iPrOH NaOMe 99 >99 Example 37 L3 .sup.iPrOH KOMe >99 >99 Example 38 L3 .sup.iPrOH .sup.tBuONa >99 >99

Example 39 Asymmetric Catalytic Hydrogenation of Aromatic Ketones

[0123] In Example 39, compound L3 was used as the ligand, sodium tert-butoxide was sued as the base, and isopropanol was used as the solvent. The reaction was schematically shown below, and the results were shown in Table 3.

##STR00026##

TABLE-US-00003 TABLE 3 Results of asymmetric catalytic hydrogenation of aromatic ketones Entry Results  1 [00027]   99% yield 98% ee  2 [00028]   99% yield 97% ee  3 [00029]   99% yield >99% ee  4 [00030]   98% yield 98% ee  5 [00031]   98% yield 98% ee  6 [00032]   99% yield >99% ee  7 [00033]   96% yield >99% ee  8 [00034]   96% yield >99% ee  9 [00035]   99% yield >99% ee 10 [00036]   99% yield >99% ee 11 [00037]   99% yield >99% ee 12 [00038]   99% yield 99% ee 13 [00039]   99% yield 99% ee 14 [00040]   99% yield 99% ee 15 [00041]   99% yield 99% ee

Example 40 Asymmetric Catalytic Hydrogenation of α-Amino Ketones

[0124] In Example 40, the ligand L3 was applied to the asymmetric hydrogenation of α-amino ketones, and the results showed that the ligand L3 had good substrate generality and application. The reaction was schematically shown below, and the results were shown in Table 4.

##STR00042##

TABLE-US-00004 TABLE 4 Results of asymmetric catalytic hydrogenation of α-amino ketones Entry Results 1 [00043]   99% yield 99% ee 2 [00044]   99% yield >99% ee 3 [00045]   98% yield 99% ee 4 [00046]   99% yield >99% ee 5 [00047]   99% yield >99% ee 6 [00048]   98% yield >99% ee 7 [00049]   99% yield >99% ee 8 [00050]   99% yield >99% ee

Example 41 Asymmetric Catalytic Hydrogenation of α-Hydrochlorinated Ketones

[0125] In Example 40, the ligand L3 was applied to the asymmetric hydrogenation of α-hydrochlorinated ketones. After optimizing the conditions, potassium carbonate was taken as the base, and a mixture of toluene and isopropanol (v/v=10:1) was used as the solvent. The reaction was schematically shown below, and the results were shown in Table 5. The results indicated that the system had good universality in asymmetric α-hydrochlorinated ketones and was promising for industrial applications.

##STR00051##

TABLE-US-00005 TABLE 5 Results of asymmetric catalytic hydrogenation of α-hydrochlorinated ketones Entry Results  1 [00052]   99% yield 98% ee  2 [00053]   99% yield 97% ee  3 [00054]   99% yield >99% ee  4 [00055]   98% yield 98% ee  5 [00056]   99% yield >99% ee  6 [00057]   96% yield >99% ee  7 [00058]   96% yield >99% ee  8 [00059]   99% yield >99% ee  9 [00060]   99% yield >99% ee 10 [00061]   99% yield 99% ee 11 [00062]   99% yield 99% ee 12 [00063]   99% yield 99% ee

[0126] The above-mentioned embodiments are preferred embodiments of the present disclosure, and these embodiments are not intended to limit the present disclosure. Any other changes, modifications, substitutions, combinations, simplifications made without departing from the spirit and principle of the present disclosure shall be equivalent substitutions and are included in the scope of protection of the present disclosure.