Chiral amino-pyridine-phosphine tridentate ligand as well as metal complex, preparation method and application thereof

Abstract

The invention provides a chiral amino-pyridine-phosphine tridentate ligand, a manganese complex as well as a preparation method and application of the chiral amino-pyridine-phosphine tridentate ligand and the manganese complex. Specifically, the invention relates to a chiral amino-pyridine-phosphine tridentate ligand as shown in a formula I. The ligand can be complexed with high-yield metal to form a metal complex, and the metal complex can be used for catalyzing asymmetric hydrogenation reaction. The metal complex catalyst provided by the invention has high catalytic activity and shows excellent enantioselectivity in an asymmetric hydrogenation reaction.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic synthesis, in particular, the present application relates to chiral amino-pyridine-phosphine tridentate ligand, its metal complex and its preparation method and application. BACKGROUND

[0002] Asymmetric catalytic hydrogenation is one of the important methods in asymmetric synthesis, which is widely used in pharmaceutical industry [Ohkuma, T.; Kitamura, M.; Noryori, R. (1999) Asymmetric Hydrogenation. In: Ojiama, I. (ed) Catalytic Asymmetric Synthesis. (2nd Ed.). Wily - VCH: New York (Englinsh) 2000], [The Handbook of Homogeneous Hydrogenation, Vol. I-III (Eds.: J. G. de Vries, C. J. Elsevier), Wiley - VCH, Weinheim, 2007]. For a long time, asymmetric catalytic hydrogenation mainly relies on ruthenium, rhodium, iridium and other noble metal catalysts. However, these noble metals are low in nature, expensive, and the use of compounds containing them in large quantities will also pollute the environment, which does not meet the green and sustainable development trend, therefore, the development of catalysis with abundant metals such as iron, manganese, cobalt and copper instead of noble metals has become a trend [Wen J.; Wang, F.; Zhang, X. Chem. Soc. Rev., 2021, 50, 3211]. Among them, manganese, the third most abundant metal element in the earth's crust, is a perfect candidate for catalysis due to its low cost, better biological compatibility and less toxicity. However, the properties of manganese are obviously different from those of noble metals, and suitable ligands need to be developed to solve the problems of activity and selectivity in catalytic hydrogenation.

[0003] Chiral secondary alcohols are important pharmacophores in medicinal chemistry and widely used synthetic intermediates. Asymmetric hydrogenation of ketones is an important method for the synthesis of chiral secondary alcohols. Although some progress has been made in manganese-catalyzed asymmetric hydrogenation of ketones [Fu, D.; Wang, Z.; Liu, Q.; Prettyman, S. J.; Solan, G. A.; Sun, W.-H. ChemCatChem 2024, e202301567], there are still some key issues to be solved. For example, the catalytic activity and enantioselectivity of some catalysts cannot be balanced, and the practicability is not high. In addition, the range of ketone compounds is generally narrow, mainly for aromatic ketone substrates, and the selectivity for alkenyl ketone substrates, especially open-chain alkenyl ketones, is poor [Wang, Z.; Zhao, X.; Huang, A.; Yang, Z.; Cheng, Y.; Chen, J.; Ling, F.; Zhong, W. Tetrahedron Lett. 2021, 82, 153389].

[0004] Therefore, there is an urgent need in the art to develop new ligands with simple structure and easy synthesis and their metal complexes as catalysts for more efficient and selective asymmetric hydrogenation of various different types of ketone compounds. SUMMARY

[0005] One object of the present application is to provide a chiral amino-pyridine-phosphine tridentate ligand.

[0006] Another object of the present application is a metal complex (particularly a manganese complex) of the chiral amino-pyridine-phosphine tridentate ligand.

[0007] Another object of the present application is to provide the use of a metal complex of the chiral amino-pyridine-phosphine tridentate ligand for catalyzing an asymmetric hydrogenation reaction.

[0008] In a first aspect of the present application, a chiral amino-pyridine-phosphine tridentate ligand represented by Formula I is provided:

[0009]

[0010] wherein * represents a chiral carbon atom, being in R configuration or S configuration;

[0011] n is an integer from 0 to 2;

[0012] R 1 is -CH-R'R", wherein R' is selected from the group consisting of H, substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl; and R" is selected from the group consisting of substituted or unsubstituted C1-C 10alkyl, substituted or unsubstituted C3to C8cycloalkyl; said substitution means that one or more hydrogens on the group are replaced by groups individually selected from the group consisting of phenyl, substituted phenyl, wherein said substitution means that said phenyl is substituted by one or more (e.g., 1, 2, 3, 4, or 5) groups individually selected from the group consisting of halogen, C1to C6alkyl, halo C1to C6alkyl, C1to C6alkoxy;

[0013] R 2 is H, halogen, C1to C 10 alkyl, C1to C 10 alkyl, C1to C 10 alkyl, C1to C 10 alkyl, C1to C 10 alkyl, C1to C

[0014] R 3 is independently substituted or unsubstituted C6to C 10 aryl, substituted or unsubstituted benzyl, wherein said substitution means that one or more hydrogen atoms on the group are replaced by groups individually selected from the group consisting of C1to C 10 alkyl, C3to C 10 cycloalkyl, or C1to C 10 alkyl, C1to C

[0015] wherein, represents the relative configuration of the C atom, when is , is when is , is

[0016] In another preferred embodiment, n is 0 or 1.

[0017] In another preferred embodiment, R' is H, substituted or unsubstituted C1to C5alkyl, substituted or unsubstituted C3to C5cycloalkyl, wherein said substitution means that one or more hydrogens on the group are replaced by groups individually selected from the group consisting of phenyl, substituted phenyl, wherein said substitution means that said phenyl is substituted by one or more groups individually selected from the group consisting of halogen, C1to C4alkyl, halo C1to C4alkyl, C1to C4alkoxy.

[0018] In another preferred embodiment, R" is substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C3-C5 cycloalkyl, wherein the substitution means that one or more hydrogens of the group are replaced by one or more groups each independently selected from the group consisting of phenyl, substituted phenyl, wherein the substitution means that the phenyl is substituted by one or more groups each independently selected from the group consisting of halogen, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy.

[0019] In another preferred embodiment, R 2 is H, halogen, C1-C4 alkyl, C1-C4 alkoxy, 4-6 membered heterocycloalkyl containing 1-3 heteroatoms each independently selected from N, O and S, substituted or unsubstituted phenyl; wherein the substitution means that one or more hydrogens of the group are replaced by one or more groups each independently selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 alkoxy.

[0020] In another preferred embodiment, R 2 is H, C1-C3 alkyl, C1-C3 alkoxy.

[0021] In another preferred embodiment, R 3 each independently is substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, wherein the substitution means that one or more hydrogen atoms of the group are replaced by one or more groups each independently selected from the group consisting of C1-C4 alkyl, C3-C6 cycloalkyl or C1-C4 alkoxy.

[0022] In another preferred embodiment, two R 3 are the same or different, preferably two R 3 are the same.

[0023] In another preferred embodiment, the ligand is selected from the group consisting of:

[0024]

[0025] In a second aspect of the present application, a process for the preparation of a ligand according to the first aspect of the present application is provided, comprising the following steps:

[0026]

[0027] (1) a compound of formula II undergoes a reductive amination reaction in the presence of a reducing agent, followed by an upper protecting group reaction with di-tert-butyl dicarbonate, to give a compound of formula III;

[0028] (2) a compound of formula III undergoes an oxidation reaction in the presence of an oxidizing agent, followed by a rearrangement reaction with a carboxylic anhydride, and finally a hydrolysis reaction in the presence of a base, to give a compound of formula IV; ​

[0029] (3) reacting the compound of formula IV with an acylating agent RSO2Cl in the presence of a base to obtain a compound of formula V;

[0030] (4) reacting the compound of formula V with a compound of formula VI in the presence of a base to obtain a compound of formula VII;

[0031] (5) deprotecting the compound of formula VII in the presence of trifluoroacetic acid and tetrafluoroboric acid to obtain a compound of formula I;

[0032] wherein,

[0033] R' and R" are as described in the first aspect of the present application;

[0034] R is selected from the group C 1-8 alkyl, C 1-6 alkyl-substituted or unsubstituted phenyl.

[0035] In another preferred embodiment, in the structure of formula V, RSO2- is a leaving group.

[0036] In another preferred embodiment, in step (1), the reducing agent is sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, or a combination thereof.

[0037] In another preferred embodiment, in step (1), the first solvent used is selected from the group consisting of C1-6alcoholic solvents, C1-6hydrocarbon solvents, C1-6halogenated hydrocarbon solvents, C2-8ethereal solvents, or a combination thereof; preferably, dichloromethane, dichloroethane, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, t-butyl methyl ether, methanol, ethanol, or a combination thereof.

[0038] In another preferred embodiment, in step (1), the reaction temperature is 0-100°C, and the reaction time is 1-48h; preferably, the reaction temperature is 10-40°C, and the reaction time is 2-30h.

[0039] In another preferred embodiment, in step (1), the molar ratio of the compound of formula II to the compound of formula 0 is 1:(1-5); preferably, the molar ratio of the compound of formula II to the compound of formula 0 is 1:(1-3.5); more preferably, 1:(1.2-3).

[0040] In another preferred embodiment, in step (1), the molar ratio of the compound of formula II to the reducing agent is 1:(1-3); preferably, 1:(1.5-2.5); more preferably, 1:2.

[0041] In another preferred embodiment, in step (2), the oxidant is selected from the group consisting of hydrogen peroxide, m-chloroperoxybenzoic acid, or combinations thereof.

[0042] In another preferred embodiment, in step (2), the carboxylic anhydride is selected from the group consisting of trifluoroacetic anhydride, acetic anhydride, or combinations thereof.

[0043] In another preferred embodiment, in step (2), the alkali is potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, sodium ethoxide, or a combination thereof.

[0044] In another preferred embodiment, in step (2), the second solvent used is selected from the group consisting of C1-6 alcohol solvents, C1-6 halocarbon solvents, C2-8 ether solvents, or combinations thereof; preferably, methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, chloroform, or combinations thereof.

[0045] In another preferred embodiment, in step (2), the reaction temperature is 0-80°C and the reaction time is 1-48h; more preferably, the reaction temperature is 10-35°C.

[0046] In another preferred embodiment, in step (2), the molar ratio of the compound of formula III to the oxidant is 1:(1-3); more preferably 1:(1-2); and even more preferably 1:1.2.

[0047] In another preferred embodiment, in step (2), the molar ratio of the compound of formula III to the carboxylic anhydride is 1:(1-3); more preferably 1:(1-2); and even more preferably 1:1.2.

[0048] In another preferred embodiment, in step (2), the molar ratio of the compound of formula III to the base is 1:(2-6); more preferably 1:(4-5.5); and even more preferably 1:(4.5-5).

[0049] In another preferred embodiment, in step (3), the third solvent used is selected from the group consisting of C1-6 halogenated hydrocarbon solvents, C2-8 ether solvents, or combinations thereof; more preferably, tetrahydrofuran, dioxane, dichloromethane, chloroform, 1,2-dichloroethane, or combinations thereof.

[0050] In another preferred embodiment, in step (3), the acylation reagent RSO2Cl is p-toluenesulfonyl chloride or methanesulfonyl chloride.

[0051] In another preferred embodiment, in step (3), the alkali is selected from the group consisting of potassium hydroxide, sodium hydroxide, silver oxide, potassium iodide, sodium iodide, or combinations thereof.

[0052] In another preferred embodiment, in step (3), the reaction temperature is 0-80°C and the reaction time is 1-48h; more preferably, the reaction temperature is 10-35°C and the reaction time is 10-40h.

[0053] In another preferred embodiment, in step (3), the molar ratio of the compound of formula IV to the base is 1:(1-5); more preferably 1:(1-3); and even more preferably 1:1.2.

[0054] In another preferred embodiment, in step (3), the molar ratio of the compound of formula IV to the acylation reagent RSO2Cl is 1:(1-3); more preferably 1:(1.2-1.8); and even more preferably 1:1.5.

[0055] In another preferred embodiment, in step (4), the fourth solvent used is selected from the group consisting of aromatic solvents, C3-8 ether solvents, or combinations thereof; preferably, toluene, tetrahydrofuran, methyl tert-butyl ether, dioxane, or combinations thereof.

[0056] In another preferred embodiment, in step (4), the reaction temperature is -80 to 60°C and the reaction time is 1 to 48 h; more preferably, the reaction temperature is -80 to 35°C and the reaction time is 10 to 48 h.

[0057] In another preferred embodiment, in step (4), the alkali is selected from the group consisting of n-butyllithium, sec-butyllithium, diisopropylaminolithium, or combinations thereof.

[0058] In another preferred embodiment, in step (4), the molar ratio of compound V to base is 1:(1-2); more preferably 1:(1-1.2); and even more preferably 1:1.

[0059] In another preferred embodiment, in step (4), the molar ratio of compound V to compound VI is 1:(1-2.5); more preferably 1:(1-1.8); and even more preferably 1:1.2.

[0060] In another preferred embodiment, in step (5), the fifth solvent used is selected from the group consisting of: aromatic solvents, C1-6 halogenated hydrocarbon solvents, C3-8 ether solvents, or combinations thereof; preferably, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, toluene, or combinations thereof.

[0061] In another preferred embodiment, in step (5), the reaction temperature is 0-80°C and the reaction time is 1-48h; more preferably, the reaction temperature is 10-40°C.

[0062] In another preferred embodiment, in step (5), the molar ratio of compound VII to trifluoroacetic acid is 1:(18-25); more preferably, it is 1:20.

[0063] In another preferred embodiment, in step (5), the molar ratio of the compound of formula VII to tetrafluoroboric acid is 1:(8-15); more preferably, it is 1:10.

[0064] In a third aspect of the invention, an intermediate for preparing the ligand of Formula I is provided, said intermediate being selected from the group consisting of:

[0065]

[0066] Among them, *, n, R, R 1 R 2 and R 3 As described in the first aspect of the present invention.

[0067] In a fourth aspect of the invention, a metal complex of formula VIII is provided;

[0068] Metal(L)(CO)2X VIII

[0069] in,

[0070] X is a chloride ion or a bromide ion;

[0071] L is

[0072] Among them, *, n, and R 1 R 2 and R 3 As described in the first aspect of the present invention;

[0073] Metal refers to metal ions.

[0074] In another preferred embodiment, Metal is a monovalent, abundant metal ion, including but not limited to: Mn + Re + Mo + ,Ir + .

[0075] In another preferred embodiment, the metal complex has the structure shown in formula VIII-a;

[0076] Mn(L)(CO)2X VIII-a

[0077] in,

[0078] X is a chloride ion or a bromide ion;

[0079] L is

[0080] Among them, *, n, and R 1 R 2 and R 3 As described in the first aspect of the present invention.

[0081] In another preferred embodiment, the complex is selected from the group consisting of:

[0082]

[0083] In a fifth aspect of the present invention, a method for preparing the manganese complex represented by formula VIII-a is provided, comprising the following steps:

[0084]

[0085] Under the protection of an inert gas, the ligand shown in Formula I reacts with a manganese metal precursor in an inert solvent to obtain the manganese complex shown in Formula VIII-a.

[0086] The manganese metal precursors mentioned above are Mn(CO)5Br and Mn(CO)5Cl;

[0087] *、R 1 ,R 2 ,R 3 And n as described in claim 1.

[0088] In another preferred embodiment, the inert solvent is selected from the group consisting of C6-C. 10 Aromatic solvents, C2-C8 ether solvents, or combinations thereof; preferably, the C6-C... 10 The aromatic solvent is toluene and / or benzene, and the C2-C8 ether solvent is selected from the group consisting of tetrahydrofuran, dioxane, tert-butyl methyl ether, or combinations thereof.

[0089] In another preferred embodiment, the molar concentration of the ligand represented by Formula I in the inert solvent is 0.05 to 2.0 mol / L, more preferably 0.05 to 1.0 mol / L, and even more preferably 0.05 to 0.2 mol / L.

[0090] In another preferred embodiment, the molar ratio of the manganese metal precursor to the ligand represented by Formula I is 1:(1-2), more preferably 1:(1-1.3), and even more preferably 1:1.

[0091] In another preferred embodiment, the reaction time is 1 to 50 hours, more preferably 1 to 20 hours.

[0092] In another preferred embodiment, the reaction temperature is 20–130°C, more preferably 80–100°C.

[0093] In a sixth aspect of the invention, a method for asymmetric catalytic hydrogenation of a compound of formula IX is provided, comprising the following steps:

[0094]

[0095] (a) In an organic solvent, under a hydrogen atmosphere, and in the presence of a base, the compound of formula IX is reduced to the compound of formula X by the catalysis of the manganese complex shown in formula VIII-a.

[0096] In the formula,

[0097] R 4 C6-C, whether substituted or unsubstituted 10 A 4-10 membered heteroaryl group, aryl, substituted or unsubstituted, containing 1-3 heteroatoms each independently selected from N, O and S; wherein the substitution refers to one or more hydrogen atoms on the group being substituted by a group selected from the group consisting of: halogen, hydroxyl, benzyloxy, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, C6-C6 10 Aryl, 4-10 membered heteroaryl containing 1-3 heteroatoms each independently selected from N, O and S;

[0098] R 5 C1 to C2, whether substituted or unsubstituted 10 Alkyl, substituted or unsubstituted C3-C8 cycloalkyl; wherein, the substitution refers to one or more hydrogen atoms on the group being substituted by a group selected from the group consisting of: halogen, hydroxyl, benzyloxy, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, C6-C6 cycloalkyl, etc. 10 Aryl, 4-10 membered heteroaryl containing 1-3 heteroatoms each independently selected from N, O and S;

[0099] Wherein, the compound of formula VIII-a is Mn(L)(CO)2X;

[0100] L and X are as described in the fourth aspect of this invention.

[0101] In another preferred embodiment, R 4 The substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5-6 membered heteroaryl group containing 1-3 heteroatoms each independently selected from N, O, and S; wherein the substitution refers to one or more hydrogen atoms on the group being substituted by a group selected from the group consisting of: halogen, hydroxyl, benzyloxy, C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy, phenyl, or a 5-6 membered heteroaryl group containing 1-3 heteroatoms each independently selected from N, O, and S.

[0102] In another preferred embodiment, R 5 The substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C5 cycloalkyl; wherein the substitution refers to one or more hydrogen atoms on the group being substituted by a group selected from the group consisting of: halogen, hydroxyl, benzyloxy, C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy, phenyl, 5-6 heteroaryl containing 1-3 heteroatoms each independently selected from N, O and S.

[0103] In another preferred embodiment, in step (a), the organic solvent is selected from the group consisting of: C1-C6 alcohol solvents, halogenated C1-C6 alcohol solvents, C2-C8 ether solvents, and C6-C6 ether solvents. 10 Aromatic hydrocarbon solvents, halogenated C1-C6 hydrocarbon solvents, or combinations thereof; preferably, methanol, ethanol, n-propanol, isopropanol, trifluoroethanol, hexafluoroisopropanol, tetrahydrofuran, dioxane, toluene, dichloromethane, or combinations thereof.

[0104] In another preferred embodiment, the pressure of the hydrogen gas is 5 to 100 atm, more preferably 10 to 60 atm, and even more preferably 30 to 50 atm.

[0105] In another preferred embodiment, the reaction temperature is 0–100°C; more preferably 25–60°C.

[0106] In another preferred embodiment, the reaction time is 1 to 100 hours, more preferably 1 to 30 hours.

[0107] In another preferred embodiment, the method includes the steps of: adding the manganese complex of formula VIII-a, the base, and the organic solvent to a high-pressure reactor under an inert gas atmosphere, further adding the compound of formula IX, sealing the reactor, purging it with hydrogen, and then carrying out the reaction.

[0108] In another preferred embodiment, the reaction further includes a post-processing step (b): purifying the compound represented by formula X by vacuum distillation, recrystallization, or column chromatography.

[0109] In another preferred embodiment, the method has one or more of the following features:

[0110] (i) The molar ratio of the compound of formula IX to the manganese complex represented by formula VIII-a is (100–40000):1, preferably (500–20000):1, and more preferably (100–15000):1; and / or

[0111] (ii) The molar concentration of the compound of formula IX in the organic solvent is 0.2–20 mol / L; preferably 0.5–5 mol / L; more preferably 0.5–2 mol / L; and / or

[0112] (iii) The molar ratio of the base to the compound of formula IX is 1:(10-1000), preferably 1:(30-100); more preferably 1:(40-60); and / or

[0113] (iv) The base is selected from the group consisting of sodium salts, potassium salts, organic bases, or combinations thereof; preferably sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium isopropoxide, potassium isopropoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, 1,8-diazabicyclo[5.4.0]undec-7-ene, 2-tert-butyl-1,1,3,3-tetramethylguanidine, or combinations thereof.

[0114] In a seventh aspect of the invention, a method for asymmetric catalytic hydrogenation of a compound of formula XI is provided, comprising the following steps:

[0115]

[0116] (c) In an organic solvent, under a hydrogen atmosphere, and in the presence of a base, the compound of formula XI is reduced to the compound of formula XII by the catalysis of the manganese complex shown in formula VIII-a.

[0117] In the formula,

[0118] R 6 R 7 and R 8 Each is independently selected from the following group: substituted or unsubstituted C1 to C1. 10 Alkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 10 A 4-10 membered heteroaryl group, aryl, substituted or unsubstituted, containing 1-3 heteroatoms each independently selected from N, O, and S; wherein the substitution refers to one or more hydrogen atoms on the group being replaced by a group selected from the group consisting of: hydroxyl, tert-butyldimethylsiloxy, halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl;

[0119] Wherein, the compound of formula VIII-a is Mn(L)(CO)2X;

[0120] L and X are as described in the fourth aspect of this invention.

[0121] In another preferred embodiment, in step (c), the organic solvent is selected from the group consisting of: C1-C6 alcohol solvents, halogenated C1-C6 alcohol solvents, C2-C8 ether solvents, and C6-C6 ether solvents. 10 Aromatic hydrocarbon solvents, halogenated C1-C6 hydrocarbon solvents, C1-C6 hydrocarbon solvents, or combinations thereof; preferably, methanol, ethanol, n-propanol, isopropanol, trifluoroethanol, hexafluoroisopropanol, tetrahydrofuran, dioxane, toluene, dichloromethane, or combinations thereof.

[0122] In another preferred embodiment, the pressure of the hydrogen gas is 5 to 100 atm, more preferably 10 to 60 atm, and even more preferably 30 to 50 atm.

[0123] In another preferred embodiment, the reaction temperature is 0–100°C; more preferably 10–40°C.

[0124] In another preferred embodiment, the reaction time is 1 to 100 h; more preferably 1 to 360 h.

[0125] In another preferred embodiment, the method includes the steps of: adding the manganese complex represented by formula VIII-a, the base, and the organic solvent to a high-pressure reactor under an inert gas atmosphere, further adding the compound represented by formula XI, sealing the reactor, purging it with hydrogen, and then carrying out the reaction.

[0126] In another preferred embodiment, the reaction further includes a post-treatment step (d): purifying the compound represented by formula XII by vacuum distillation, recrystallization, or column chromatography.

[0127] In another preferred embodiment, the method has one or more of the following features:

[0128] (i) The molar ratio of the compound represented by formula XI to the manganese complex represented by formula VIII is (50–5000):1, preferably (100–1000):1, and more preferably (100–500):1; and / or

[0129] (ii) The molar concentration of the compound represented by formula XI in the organic solvent is 0.2–2 mol / L; preferably 0.5–1 mol / L; and / or

[0130] (iii) The molar ratio of the base to the compound represented by formula XI is 1:(10-100), preferably 1:(20-50); and / or

[0131] (iv) The base is selected from the group consisting of sodium salts, potassium salts, organic bases, or combinations thereof; preferably sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium isopropoxide, potassium isopropoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, 1,8-diazabicyclo[5.4.0]undec-7-ene, 2-tert-butyl-1,1,3,3-tetramethylguanidine, or combinations thereof.

[0132] In another preferred embodiment, R 6 Selected from the following group: substituted or unsubstituted C1 to C2 10 Alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C6-C 10A 5-7 membered heteroaryl group, aryl, substituted or unsubstituted, containing 1-3 heteroatoms each independently selected from N, O, and S; wherein the substitution refers to one or more hydrogen atoms on the group being replaced by a group selected from the group consisting of: hydroxyl, tert-butyldimethylsiloxy, halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl group.

[0133] In another preferred embodiment, R 8 Selected from the group consisting of C1-C4 alkyl, substituted or unsubstituted phenyl groups; wherein, substitution refers to one or more hydrogen atoms on the group being replaced by a group selected from the group consisting of: hydroxyl, tert-butyldimethylsiloxy, halogen, C 1-6 Alkyl, C 1-6 Alkyl group.

[0134] In another preferred embodiment, R 7 Selected from the following group: C1-C4 alkyl, phenyl.

[0135] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0136] Through extensive and in-depth research, the inventors have, for the first time, provided a novel metal catalyst for asymmetric hydrogenation reactions. Specifically, the metal catalyst provided by this invention is composed of a novel chiral amino-pyridine-phosphine tridentate ligand and a readily available metal complex, and can be used to catalyze the asymmetric hydrogenation of aryl ketones and alkenyl ketones. The catalyst of this invention exhibits excellent catalytic activity and enantioselectivity in the asymmetric hydrogenation of aryl ketones, and excellent chemoselectivity and enantioselectivity in the asymmetric hydrogenation of alkenyl ketones, thus possessing broad application value. Based on this, the inventors completed this invention.

[0137] the term

[0138] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0139] As used in this article, the term "room temperature" generally refers to 4-30°C, preferably 20±5°C.

[0140] As used herein, the term "alkyl" itself, or as part of another substituent, refers to a straight-chain or branched hydrocarbon group having a specified number of carbon atoms (e.g., C1-C1). 18Alkyl groups are C1-C8, C1-C6, or C1-C4, where C1-C8 represents 1-8 carbons. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc.

[0141] In this invention, the term "C2-C6 alkenyl" refers to a straight-chain or branched alkenyl group having 2-6 carbon atoms and containing a double bond, and includes, without limitation, vinyl, propenyl, butenyl, isobutenyl, pentenyl, and hexenyl groups.

[0142] In this invention, the term "C1-C6 alkoxy" refers to a straight-chain or branched alkoxy group having 1-6 carbon atoms, and includes, without limitation, methoxy, ethoxy, propoxy, isopropoxy, and butoxy. Preferably, it is a C1-C4 alkoxy group.

[0143] As used herein, the term "aryl" refers to an aromatic group whose ring skeleton consists entirely of carbon atoms, such as C6-C. 20 Aryl groups, representative examples of which are phenyl, naphthyl, anthraceneyl, and phenanthrene, are also included in this invention. In this invention, the aryl group further includes groups in which one or more H atoms on the aryl group are replaced by substituents selected from the group consisting of halogens, phenyl groups, unsubstituted or halogen-substituted C atoms. 1-6 Alkyl, unsubstituted, or C substituted with one or more halogens 1-6 Alkyl group.

[0144] As used herein, the term "heteroaryl" refers to an aromatic group whose ring skeleton includes at least one heteroatom (the remainder may be carbon atoms), such as 4-20 membered heteroaryls, representative examples being pyridyl, thiophene, indolyl, and furanyl. In this invention, the heteroaryl also includes groups in which one or more H atoms on the heteroaryl group are substituted by substituents selected from the group consisting of halogens, phenyl groups, unsubstituted or C atoms substituted with one or more halogens. 1-6 Alkyl, unsubstituted, or C substituted with one or more halogens 1-6 Alkyl group.

[0145] As used herein, the term "cycloalkyl" refers to a saturated cyclic group whose cyclic skeleton consists entirely of carbon atoms, such as C3-C4. 18 Cycloalkyl groups (preferably C3-C8 or C3-C6 cycloalkyl groups), representative examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. In this invention, the cycloalkyl group further includes groups in which one or more H atoms on the cycloalkyl group are substituted by substituents selected from the group consisting of halogens, phenyl groups, unsubstituted or substituted C atoms with one or more halogens. 1-6 Alkyl, unsubstituted, or C substituted with one or more halogens 1-6 Alkyl group.

[0146] In this invention, the term "heterocyclic alkyl" refers to a 4-8 membered heterocyclic alkyl group containing 1, 2, or 3 heteroatoms selected from N, O, and S, including (but not limited to) the following groups: The term "4-10 membered heterocyclic alkyl group containing 1-4 heteroatoms selected from N, O, and S" has a similar meaning.

[0147] As used herein, the term "one or more" generally refers to 1-6; preferably 1-5; and more preferably 1-3.

[0148] As used in this article, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0149] As used herein, the terms “containing” or “including (comprise)” can be open-ended, semi-closed, or closed. In other words, the terms also include “consistently made of” or “made of”.

[0150] Generally, the upper limit of the ee value of a compound is no more than 99.9%. In this invention,

[0151] The term "substitution" refers to the replacement of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent is the substituent described accordingly above, or the substituent appearing in the various examples. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents may be the same or different at each position. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are those that are stable or chemically feasible. Such substituents include, but are not limited to: halogens, hydroxyl groups, carboxyl groups (-COOH), C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C8 cycloalkyl groups, 3- to 12-membered heterocyclic groups, aryl groups, heteroaryl groups, C1-C8 aldehyde groups, amino groups, C1-C6 alkoxy groups, etc.

[0152] Catalysts: Chiral amino-pyridine-phosphine tridentate ligands and their manganese complexes

[0153] This invention discloses a novel structure comprising pyridinocycle The present invention relates to a chiral amino-pyridine-phosphine tridentate ligand and its metal complex, wherein the structure of the chiral amino-pyridine-phosphine tridentate ligand is shown in Formula I. The metal complex is formed by complexing the chiral amino-pyridine-phosphine tridentate ligand with an abundant metal (e.g., iron, copper, cobalt, and manganese), preferably with manganese to form a manganese complex.

[0154] Specifically, the structure of the chiral amino-pyridine-phosphine tridentate ligand (L) is as follows:

[0155]

[0156] In the formula, each group is as described above.

[0157] The metal complex has the structure shown in Formula VIII:

[0158] Metal(L)(CO)2X VIII

[0159] in,

[0160] L is the chiral amino-pyridine-phosphine tridentate ligand shown in Formula I;

[0161] X is a chloride ion or a bromide ion;

[0162] Metal is a metal ion selected from the following group: Mn + Re + Mo + ,Ir + Preferably, the metal ion is Mn. + .

[0163] Preferably, the metal complex has the structure shown in formula VIII-a:

[0164] Mn(L)(CO)2X VIII-a

[0165] Preparation method of chiral amino-pyridine-phosphine tridentate ligands and their manganese complexes

[0166] This invention also provides a method for preparing manganese complexes of chiral amino-pyridine-phosphine tridentate ligands, specifically comprising the following steps:

[0167]

[0168] Under the protection of an inert gas, the ligand shown in Formula I reacts with a manganese metal precursor in an inert solvent to obtain the manganese complex shown in Formula VIII-a.

[0169] The manganese metal precursors mentioned above are Mn(CO)5Br and Mn(CO)5Cl.

[0170] In the method described, the inert gas is an inert gas conventionally used in the art, preferably one or more of nitrogen, helium, and argon.

[0171] In the preparation method described above, the organic solvent is a conventional solvent for this type of reaction in the art, preferably one or more of aromatic solvents and ether solvents. The aromatic solvent is preferably toluene and / or benzene, and the ether solvent is preferably one or more of tetrahydrofuran, dioxane, and tert-butyl methyl ether.

[0172] In the preparation method described above, the amount of organic solvent used is the conventional amount used in this type of reaction in the art. Preferably, the molar concentration of the chiral amino-pyridine-phosphine tridentate ligand represented by Formula I in the organic solvent is 0.05-2.0 mol / L, more preferably 0.05-1.0 mol / L, and even more preferably 0.05-0.2 mol / L.

[0173] In the preparation method described above, the amount of manganese metal precursor used is the conventional amount used in this type of reaction in the art. Preferably, the molar ratio of the manganese metal precursor to the chiral amino-pyridine-phosphine tridentate ligand shown in Formula I is 1:1 to 2, more preferably 1:1 to 1.3.

[0174] In the preparation method described above, the reaction temperature is the conventional reaction temperature for this type of reaction in the art, preferably 20-130°C, and more preferably 80-120°C.

[0175] In the preparation method described above, the reaction time is the conventional reaction time for this type of reaction in the art, preferably 1 to 50 hours, and more preferably 1 to 20 hours.

[0176] Application: Catalytic asymmetric hydrogenation reaction

[0177] The manganese complex of the chiral amino-pyridine-phosphine tridentate ligand of the present invention can be used to catalyze various types of asymmetric hydrogenation reactions, such as asymmetric hydrogenation reactions of aryl ketones or alkenyl ketones.

[0178] Specifically, the asymmetric hydrogenation reaction of aryl ketones includes the following steps.

[0179]

[0180] (a) In an organic solvent, under a hydrogen atmosphere, and in the presence of a base, the compound of formula IX is reduced to the compound of formula X by the catalysis of the manganese complex shown in formula VIII-a, wherein the definitions of each group are as described above.

[0181] Post-processing steps: (b) The compound represented by formula X is purified by vacuum distillation, recrystallization or column chromatography.

[0182] In a preferred embodiment, the reaction includes the following steps:

[0183] In an inert gas atmosphere, the manganese complex represented by formula VIII-a, the alkali, and the organic solvent are added to a high-pressure reactor, and the compound of formula IX is further added. After sealing the reactor, hydrogen is introduced to carry out the reaction.

[0184] Specifically, the asymmetric hydrogenation reaction of alkenyl ketones includes the following steps:

[0185]

[0186] (c) In an organic solvent, under a hydrogen atmosphere, and in the presence of a base, the compound of formula XI is reduced to the compound of formula XII by the catalysis of the manganese complex shown in formula VIII-a, wherein the definitions of each group are as described above.

[0187] Post-processing steps: (d) The compound represented by formula XII is purified by vacuum distillation, recrystallization or column chromatography.

[0188] In a preferred embodiment, the reaction includes the following steps:

[0189] In an inert gas atmosphere, the manganese complex represented by formula VIII-a, the alkali, and the organic solvent are added to a high-pressure reactor, and the compound represented by formula XI is further added. After sealing the reactor, hydrogen is introduced to carry out the reaction.

[0190] The manganese complex of the present invention is mainly used for catalyzing asymmetric hydrogenation reactions. Generally, the reaction system mainly includes hydrogen and alkali. In one embodiment of the present invention, the pressure of hydrogen in the reaction system can be conventionally selected, generally 5 to 100 atm, preferably 10 to 60 atm, and more preferably 30 to 50 atm.

[0191] In another embodiment, the base is a base commonly used in asymmetric hydrogenation reactions, including but not limited to sodium salts, potassium salts, organic bases, or combinations thereof; preferably sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium isopropoxide, potassium isopropoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, 1,8-diazabicyclo[5.4.0]undec-7-ene, 2-tert-butyl-1,1,3,3-tetramethylguanidine, or combinations thereof.

[0192] In another embodiment, the organic solvent for the reaction can be conventionally selected according to the reaction type, such as C1-C6 alcohol solvents, halogenated C1-C6 alcohol solvents, C2-C8 ether solvents, C6-C6 ether solvents, etc. 10 Aromatic hydrocarbon solvents, halogenated C1-C6 hydrocarbon solvents, C1-C6 hydrocarbon solvents, or combinations thereof; preferably, methanol, ethanol, n-propanol, isopropanol, trifluoroethanol, hexafluoroisopropanol, tetrahydrofuran, dioxane, toluene, dichloromethane, or combinations thereof.

[0193] The reaction time and temperature of the asymmetric hydrogenation reaction of the present invention can be conventionally selected according to the reaction type and reaction scale. In one specific embodiment, the reaction temperature is 0-100℃; preferably 25-60℃. The reaction time is 1-100h, preferably 1-30h.

[0194] In the symmetrical hydrogenation reaction of this invention, the amount of catalyst (i.e., the metal complex shown in Formula VIII) is very small, generally on the order of one-thousandth to one-ten-thousandth of the aryl ketone or alkenyl ketone raw material. The amount of base can be conventionally selected based on the amount of reactants. The amount of organic solvent can also be conventionally selected based on the amount of reactants, and there are no particular limitations as long as the reaction proceeds normally.

[0195] Compared with the prior art, the main advantages of the present invention include:

[0196] (1) This invention provides a class of easily synthesized chiral amino-pyridine-phosphine tridentate ligands and their metal complexes (especially manganese complexes).

[0197] (2) The chiral amino-pyridine-phosphine tridentate ligand and its metal complex provided by the present invention have a simple synthesis process, good stability, high catalytic activity and mild reaction conditions.

[0198] (3) The product yield and ee value of the metal complex catalyzed asymmetric hydrogenation reaction of the present invention are high.

[0199] (4) The manganese complex of the present invention not only exhibits excellent catalytic activity and enantioselectivity in the asymmetric hydrogenation of aryl ketones, but also exhibits excellent chemoselectivity and enantioselectivity in the asymmetric hydrogenation of alkenyl ketones.

[0200] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0201] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0202] Example 1: Synthesis of chiral amine (R)-IIa

[0203]

[0204] Under an argon atmosphere, 4.6 g (27.2 mmol) of 2-chloro-6,7-dihydro-5H-cyclopentano[B]pyridine-7-ol and 3.5 M methylcycloboroxane (3.5 M in) were added to a 200 mL Schlenk flask that had been treated to be anhydrous and oxygen-free. THF (15.5 mL, 54.4 mmol), Pd(dppf)Cl2·CH2Cl2 (1.1 g, 1.36 mmol), potassium carbonate (11.3 g, 81.6 mmol), 1,4-dioxane solution (96 mL), and water (16 mL) were added. The mixture was then rapidly purged with argon three times and reacted at 100 °C for 4 h. After the reaction was complete, water was added to the system, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was separated by column chromatography (petroleum ether / ethyl acetate = 1:1) to give 3.82 g of a brown solid, 2-methyl-6,7-dihydro-5H-cyclopentano[B]pyridin-7-ol, with a yield of 94%. 1 H NMR (400MHz, CDCl3): δ7.46(d,J=8.0Hz,1H),7.01(d,J=7.6Hz,1H),5.21(t,J=6.8Hz,1H),4.26(br s,1H),3.07-2.93(m,1H),2.83-2.72(m,1H),2.66-2.45(m,5H),2.12-1.97(m,1H)ppm; HRMS(ESI):calcd.for[C9H 12 NO] + ([M+H)) + ):150.09134,found:150.09084.

[0205] Under an argon atmosphere, 2-methyl-6,7-dihydro-5H-cyclopentano[B]pyridin-7-ol (4.0 g, 27.0 mmol) and THF (45 mL) were added to a 200 mL Schlenk flask that had been treated to be anhydrous and oxygen-free. After cooling to 0 °C, DPPA (7.6 mL, 35.1 mmol) and DBU (4.8 mL, 32.4 mmol) were added, and the reaction was carried out at room temperature for 12 h. After the reaction was complete, the system was quenched with water. The mixture was extracted with dichloromethane (20 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate. After filtration, the solvent was removed under reduced pressure to obtain the crude product. Tetrahydrofuran (80 mL), PPh3 (14.3 g, 54.4 mmol), and water (8 mL) were added to the crude product, and the reaction was carried out at room temperature for 12 h. After the reaction was complete, the mixture was extracted with dichloromethane (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was separated by column chromatography (dichloromethane / methanol = 15:1) to give 2.52 g of 2-methyl-6,7-dihydro-5H-cyclopentano[B]pyridine-7-amine IIa, with a yield of 63%. 1 H NMR (400MHz, CDCl3): δ7.40(d,J=8.0Hz,1H),6.95(d,J=8.0Hz,1H),4.30(t,J=7.6Hz,1H),3.01-2.90(m, 1H),2.79-2.69(m,1H),2.54(s,3H),2.18-1.91(m,3H),1.82-1.69(m,1H)ppm; HRMS(ESI):calcd.for[C9H 13 N2] + ([M+H)) + ):149.10732,found:149.10683.

[0206] Example 2: Synthesis of chiral amine (R)-IIb

[0207]

[0208] For detailed instructions, please refer to Example 1. Yield: 75%. Yellow oily liquid. 1 H NMR (400MHz, CDCl3): δ6.80(s,1H),4.29(t,J=7.6Hz,1H),2.91-2.82(m,1H),2.73-2.62(m,1H),2.59-2.47(m,4H),2.22(s,3H),2.10(br s,2H),1.81-1.69(m,1H)ppm; HRMS(ESI)calcd.for[C 10 H 15 N2]+ ([M+H)) + ):163.12297,found:163.12365.

[0209] Example 3: Synthesis of chiral amine (R)-IId

[0210]

[0211] For detailed instructions, please refer to Example 1. Yield: 71%. Yellow oily liquid. 1 H NMR (400MHz, CDCl3): δ6.82(s,1H),3.84(t,J=6.4Hz,1H),2.84-2.60(m,2H),2.48(s,3H),2.26-1.91(m,7H),1.86-1.70(m,2H)ppm; HRMS(ESI)calcd.for[C 11 H 17 N2] + ([M+H)) + ):177.13862,found:177.13806.

[0212] Example 4: Synthesis of chiral amine (S)-IIa

[0213]

[0214] For detailed instructions, please refer to Example 1. Yield: 68%. Yellow oily liquid. 1 H NMR (400MHz, CDCl3): δ7.40(d,J=8.0Hz,1H),6.95(d,J=8.0Hz,1H),4.30(t,J=7.6Hz,1H),3.01-2.90(m, 1H),2.79-2.69(m,1H),2.54(s,3H),2.18-1.91(m,3H),1.82-1.69(m,1H)ppm; HRMS(ESI):calcd.for[C9H 13 N2] + ([M+H)) + ):149.10732,found:149.10704.

[0215] Example 5: Synthesis of compound (R)-IIIa

[0216]

[0217] Take a 50 mL round-bottom flask, add (R)-IIa (1.57 g, 10.6 mmol), then add THF (30 mL), potassium carbonate (1.76 g, 12.7 mmol) and isobutyraldehyde (2.9 mL, 31.8 mmol) in sequence, and react at room temperature for 5 h. 1 After complete conversion of (R)-IIa as monitored by ¹H NMR, the mixture was filtered, and the solvent was removed under reduced pressure. Anhydrous methanol (30 mL) was added to the residue, followed by the addition of NaBH₄ (800 mg, 21.2 mmol) at 0 °C. Extensive bubble generation was observed, and the mixture was heated to room temperature for 5 h. The solution was quenched with water, extracted three times with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate. After filtration, the solvent was removed under reduced pressure. The residue was then reacted with dichloromethane (30 mL) and Boc₂O (3.7 mL, 15.9 mmol) at room temperature for 16 h. After complete substrate conversion as monitored by TLC, the solvent was removed under reduced pressure. The resulting residue was separated by column chromatography (petroleum ether / ethyl acetate = 5:1) to give 2.02 g of a colorless oily liquid (R)-IIIa, with a yield of 63%. 1 H NMR (400MHz, CDCl3): δ7.42-7.28(m,1H),6.92(d,J=8.0Hz,1H),5.25-4.55(m,1H)3.54-2.64( m,4H),2.57-2.13(m,5H),2.02-1.82(m,1H),1.56-0.70(m,15H)ppm; HRMS(ESI):calcd.for[C 18 H 28 N2O2Na] + ([M+Na)) + ):327.20430,found:327.20386.

[0218] Example 6: Synthesis of compound (R)-IIIb

[0219]

[0220] For detailed instructions, please refer to Example 5. Yield: 72%. Colorless liquid. 1 H NMR (400MHz, CDCl3): δ6.88(s,1H),5.25-4.62(m,1H)3.56-2.65(m,4H),2.57-2 .13(m,8H),2.02-1.82(m,1H),1.56-0.70(m,15H)ppm; HRMS(ESI):calcd.for[C 19 H 31 N2O2] + ([M+H)) +):319.23800,found:319.23738.

[0221] Example 7: Synthesis of compound (R)-IIIc

[0222]

[0223] For detailed instructions, please refer to Example 5. The product is a colorless, viscous liquid with a yield of 89%. 1 H NMR (400MHz, CDCl3): δ7.18 (d, J = 8.0Hz, 1H), 6.92-6.81 (m, 1H), 4.99-4.17 (m, 1H), 3.38-2.60 (m, 4H) ,2.42(s,3H),2.30-1.84(m,4H),1.82-1.61(m,1H),1.54-0.76(m,15H)ppm; HRMS(ESI):calcd.for[C 19 H 30 N2O2Na] + ([M+Na)) + ):341.21995,found:341.22080.

[0224] Example 8: Synthesis of compound (R)-IIId

[0225]

[0226] For detailed instructions, please refer to Example 5. The product is a colorless, viscous liquid with a yield of 82%. 1 H NMR (400MHz, CDCl3): δ6.87(s,1H),4.90-4.16(m,1H),3.35-2.60(m,4H),2.40(s,3H),2.31-1.61(m,8H),1.54-0.71(m,15H)ppm; HRMS(ESI):calcd.for[C 20 H 33 N2O2] + ([M+H)) + ):333.25365,found:333.25412.

[0227] Example 9: Synthesis of compound (R)-IIIe

[0228]

[0229] Amine (R)-IIa (276 mg, 1.86 mmol), 1,2-dichloroethane (4 mL), acetone (165 μL, 2.24 mmol), sodium triacetoxyborohydride (792 mg, 3.73 mmol), and acetic acid (107 μL, 1.86 mmol) were added sequentially to a 25 mL single-necked flask. The reaction mixture was stirred at room temperature for 10 h. The reaction was quenched with a saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain a crude product. Dichloromethane (4 mL) and Boc₂O (0.84 mL, 3.72 mmol) were added to the crude product. The mixture was stirred at room temperature for 48 h. The solvent was removed under reduced pressure, and the residue was separated by column chromatography (petroleum ether / ethyl acetate = 10:1) to give a colorless oily liquid (R)-IIIe 298 mg, yield 56%. 1 H NMR (400MHz, CDCl3): δ7.38-7.28(m,1H),6.90(d,J=7.6Hz,1H),5.45-4.35(m,2H),2.97-2.86 (m,1H),2.83-2.72(m,1H),2.54-2.10(m,5H),1.40-0.90(m,15H)ppm; HRMS(ESI):calcd.for[C 17 H 27 N2O2] + ([M+H)) + ):291.20670,found:291.20612.

[0230] Example 10: Synthesis of compound (R)-IIIf

[0231]

[0232] For detailed instructions, please refer to Example 9. Yield: 78%. Colorless liquid. 1 H NMR (400MHz, CDCl3): δ6.86 (s, 1H), 5.47-4.32 (m, 2H), 2.95-2.73 (m, 2H), 2.54-2.10 (m, 8H), 1.42-0.89 (m, 15H) ppm; HRMS (ESI): calcd.for[C 18 H 29 N2O2] + ([M+H)) + ):305.22235,found:305.22174.

[0233] Example 11: Synthesis of compound (R)-IIIg

[0234]

[0235] For detailed instructions, please refer to Example 9. Yield: 96%. Colorless liquid. 1 H NMR (400MHz, CDCl3): δ7.25-7.14(m,1H),6.86(d,J=7.2Hz,1H),5.10-4.15(m,2H),2.82-2.62(m,2H),2.45-2.37 (m,3H),2.35-2.20(m,1H),2.12-1.92(m,2H),1.80-1.66(m,1H),1.54-0.95(m,15H)ppm; HRMS(ESI):calcd.for[C 18 H 29 N2O2] + ([M+H)) + ):305.22235,found:305.22186.

[0236] Example 12: Synthesis of compound (R)-IIIh

[0237]

[0238] For detailed instructions, please refer to Example 9. Yield: 90%. Colorless liquid. 1 H NMR (400MHz, CDCl3): δ6.85(s,1H),5.06-4.13(m,2H),2.81-2.65(m,2H),2.47-2.19(m,7 H),2.10-1.92(m,2H),1.81-1.66(m,1H),1.55-0.94(m,15H)ppm; HRMS(ESI):calcd.for[C 19 H 31 N2O2] + ([M+H)) + ):319.23800,found:319.23756.

[0239] Example 13: Synthesis of compound (R)-IVa

[0240]

[0241] (R)-IIIa (1.38 g, 4.53 mmol) and dichloromethane (20 mL) were added to a 100 mL round-bottom flask. 3-chloroperoxybenzoic acid (1.1 g, 5.44 mmol) was added at 0 °C, and the mixture was stirred overnight at room temperature. After the reaction was complete, sodium thiosulfate solution (4 M, 20 mL) and saturated sodium bicarbonate solution (50 mL) were added sequentially to quench the reaction. The mixture was separated, and the aqueous phase was extracted with dichloromethane (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the residue. The crude product was added to a 100 mL Schlenk flask that had been treated to be anhydrous and oxygen-free. After purging with argon, THF (40 mL) was added. After cooling to 0 °C, trifluoroacetic anhydride (0.76 mL, 5.44 mmol) was added, and the mixture was reacted at room temperature for 2 h. After the reaction was complete, the solvent was removed under reduced pressure, and methanol (20 mL) and potassium carbonate (3.2 g, 22.85 mmol) were added. The reaction was allowed to proceed at room temperature for 20 h. After the reaction was complete, the reaction was quenched with water, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was separated by column chromatography (dichloromethane / ethyl acetate = 1:1) to give a yellow oily liquid (R)-IVa 976 mg. The yield was 68%. 1 HNMR (400MHz, CDCl3): δ7.47(d,J=7.6Hz,1H),7.01(d,J=8.0Hz,1H),5.17-4.04(m,4H),3.45-2. 72(m,4H),2.58-2.24(m,2H),2.08-1.75(m,1H),1.55-0.76(m,15H)ppm; HRMS(ESI):calcd.for[C 18 H 28 N2O3Na] + ([M+Na)) + ):343.19921,found:343.19913.

[0242] Example 14: Synthesis of compound (R)-IVb

[0243]

[0244] For detailed instructions, please refer to Example 13. The product is a yellow, oily liquid with a yield of 68%. 1 H NMR (400MHz, CDCl3): δ6.98(s,1H),5.24-4.03(m,4H),3.49-2.70(m,4H),2.59- 2.20(m,5H),2.06-1.72(m,1H),1.51-0.73(m,15H)ppm; HRMS(ESI):calcd.for[C18 H 30 N2O3Na] + ([M+Na)) + ):357.21486,found:357.21505.

[0245] Example 15: Synthesis of compound (R)-IVc

[0246]

[0247] For detailed instructions, please refer to Example 13. The product is a colorless, viscous liquid with a yield of 70%. 1 H NMR (400MHz, CDCl3): δ7.40-7.32(m,1H),7.01-6.88(m,1H),5.11-3.99(m,4H),3.46-3.01(m ,2H),2.98-2.68(m,2H),2.34-1.64(m,5H),1.53-0.84(m,15H)ppm; HRMS(ESI):calcd.for[C 19 H 30 N2O3Na] + ([M+Na)) + ):357.21486,found:357.21547.

[0248] Example 16: Synthesis of compound (R)-IVd

[0249]

[0250] For detailed instructions, please refer to Example 13. The product is a colorless, viscous liquid with a yield of 66%. 1 H NMR(400MHz, CDCl3): δ6.89(s,1H),5.19-3.89(m,4H),3.48-2.69(m,4H),2.34-1.64(m,8H),1.50-0.81(m,15H)ppm; HRMS(ESI):calcd.for[C 20 H 32 N2O3Na] + ([M+Na)) + ):371.23051,found:371.23137.

[0251] Example 17: Synthesis of compound (R)-IVe

[0252]

[0253] For detailed instructions, please refer to Example 13. The product is a colorless, viscous liquid with a yield of 68%.1 H NMR (400MHz, CDCl3): δ7.46 (d, J=7.2Hz, 1H), 6.96 (d, J=7.2Hz, 1H), 5.20-4.10 (m, 5H), 3.08-2.76(m,2H),2.45-2.25(m,2H),1.50-0.86(m,15H)ppm; HRMS(ESI):calcd.for[C 17 H 26 N2O3Na] + ([M+Na)) + ):329.18356,found:329.18287.

[0254] Example 18: Synthesis of compound (R)-IVf

[0255]

[0256] For detailed instructions, please refer to Example 13. The product is a colorless, viscous liquid with a yield of 70%. 1 H NMR (400MHz, CDCl3): δ6.90 (s, 1H), 5.20-4.14 (m, 5H), 3.10-2.73 (m, 2H), 2.45-2.20 (m, 5H), 1.50-0.83 (m, 15H) ppm; HRMS (ESI): calcd.for[C 18 H 28 N2O3Na] + ([M+Na)) + ):343.19921,found:343.19914.

[0257] Example 19: Synthesis of compound (R)-IVg

[0258]

[0259] For detailed instructions, please refer to Example 13. The product is a colorless, viscous liquid with a yield of 63%. 1 HNMR (400MHz, CDCl3): δ7.36-7.31(m,1H),6.94-6.87(m,1H),4.70-4.10(m,5H),2.95-2.65(m,2H),2. 38-2.20(m,1H),2.14-1.98(m,2H),1.86-1.68(m,1H),1.48-0.95(m,15H)ppm; HRMS(ESI):calcd.for[C 18 H 28 N2O3Na] + ([M+Na))+ ):343.19921,found:343.19876.

[0260] Example 20: Synthesis of compound (R)-IVh

[0261]

[0262] For detailed instructions, please refer to Example 13. The product is a colorless, viscous liquid with a yield of 65%. 1 HNMR (400MHz, CDCl3): δ6.90 (s, 1H), 4.75-4.10 (m, 5H), 2.93-2.66 (m, 2H), 2.38-2.17 (m, 4 H),2.13-1.89(m,2H),1.84-1.69(m,1H),1.48-0.95(m,15H)ppm; HRMS(ESI):calcd.for[C 19 H 30 N2O3Na] + ([M+Na)) + ):357.21486,found:357.21445.

[0263] Example 21: Synthesis of compound (R)-Va

[0264]

[0265] Under an argon atmosphere, silver oxide (630 mg, 2.72 mmol), potassium iodide (91 mg, 0.55 mmol), compound (R)-IVa (877 mg, 2.74 mmol), dichloromethane solution (15 mL), and p-toluenesulfonyl chloride (779 mg, 4.09 mmol) were added sequentially to a 50 mL Schlenk flask that had been treated to be anhydrous and oxygen-free. The reaction was carried out in the dark for 16 h. After complete conversion of the starting material as monitored by TLC, the mixture was filtered through diatomaceous earth, washed with ethyl acetate, and the solvent was removed from the filtrate under reduced pressure. The residue was separated by column chromatography (petroleum ether / ethyl acetate = 10:1) to give 1.22 g of a colorless oily liquid (R)-Va, with a yield of 94%. 1 H NMR (400MHz, CDCl3): δ7.83(d,J=7.6Hz,2H),7.47(d,J=7.6Hz,1H),7.35(d,J=7.6Hz,2H),7.26-7.11(m,1H),5.20-4 .49(m,3H),3.40-2.67(m,4H),2.56-2.18(m,5H),1.97-1.67(m,1H),1.50-0.75(m,15H)ppm; HRMS(ESI):calcd.for[C 25H 34 [N2O5NaS] + ([M+Na)) + ):497.20806,found:497.20797.

[0266] Example 22: Synthesis of compound (R)-Vb

[0267]

[0268] For detailed instructions, please refer to Example 21. The product is a colorless, viscous liquid with a yield of 89%. 1 H NMR (400MHz, CDCl3): δ7.85(d,J=7.6Hz,2H),7.33(d,J=7.6Hz,2H),7.14(s,1H),5.22-4.47(m,3H),3. 43-2.69(m,4H),2.51-2.11(m,8H),1.99-1.65(m,1H),1.50-0.78(m,15H)ppm; HRMS(ESI):calcd.for[C 26 H 36 [N2O5NaS] + ([M+Na)) + ):511.22371,found:511.22295.

[0269] Example 23: Synthesis of compound (R)-Vc

[0270]

[0271] For detailed instructions, please refer to Example 21. The product is a colorless, viscous liquid with a yield of 90%. 1 H NMR (400MHz, CDCl3): δ7.81 (d, J = 8.4Hz, 2H), 7.38-7.28 (m, 3H), 7.23-7.03 (m, 1H), 5.06-4.93 (m, 2H), 4.77-4.12 (m, 1H), 3.26-2. 64(m,4H),2.45(s,3H),2.27-2.08(m,2H),2.06-1.82(m,2H),1.77-1.63(m,1H),1.46-0.84(m,15H)ppm; HRMS(ESI):calcd.for[C 26 H 36 [N2O5NaS] + ([M+Na)) + ):511.22371,found:511.22380.

[0272] Example 24: Synthesis of compound (R)-Vd

[0273]

[0274] For detailed instructions, please refer to Example 21. The product is a colorless, viscous liquid with a yield of 91%. 1 H NMR (400MHz, CDCl3): δ7.81 (d, J = 8.4Hz, 2H), 7.38-7.28 (m, 3H), 7.23-7.03 (m, 1H), 5.06-4.93 (m, 2H), 4.77-4.12 (m, 1H), 3.26-2. 64(m,4H),2.45(s,3H),2.27-2.08(m,2H),2.06-1.82(m,2H),1.77-1.63(m,1H),1.46-0.84(m,15H)ppm; HRMS(ESI):calcd.for[C 27 H 38 [N2O5NaS] + ([M+Na)) + ):525.23936,found:525.23849.

[0275] Example 25: Synthesis of compound (R)-Ve

[0276]

[0277] For detailed instructions, please refer to Example 21. The product is a colorless, viscous liquid with a yield of 89%. 1 H NMR (400MHz, CDCl3): δ7.83(d,J=8.0Hz,2H),7.46(d,J=7.6Hz,1H),7.35(d,J=8.0Hz,2H),7.23-7.12(m,1H ),5.15-4.40(m,3H),3.02-2.73(m,2H),2.47-2.25(m,5H),1.28-0.78(m,15H)ppm; HRMS(ESI):calcd.for[C 24 H 32 [N2O5NaS] + ([M+Na)) + ):483.19241,found:483.19272.

[0278] Example 26: Synthesis of compound (R)-Vf

[0279]

[0280] For detailed instructions, please refer to Example 21. The product is a colorless, viscous liquid with a yield of 91%.1 H NMR (400MHz, CDCl3): δ7.82(d,J=8.0Hz,2H),7.33(d,J=8.0Hz,2H),7.23-7.10(m,1H),5.10-4.3 7(m,3H),3.03-2.71(m,2H),2.49-2.20(m,5H),1.30-0.76(m,15H)ppm; HRMS(ESI):calcd.for[C 25 H 34 [N2O5NaS] + ([M+Na)) + ):497.20806,found:497.20763.

[0281] Example 27: Synthesis of compound (R)-Vg

[0282]

[0283] For detailed instructions, please refer to Example 21. The product is a colorless, viscous liquid with a yield of 95%. 1 HNMR (400MHz, CDCl3): δ7.81(d,J=8.0Hz,2H),7.38-7.30(m,3H),7.20-7.05(m,1H),5.07-4.91(m,2H),4.84-4.41(m,1H),4.20-3.49(m,1H) ),2.90-2.65(m,2H),2.45(s,3H),2.35-2.21(m,1H),2.10-1.94(m,2H),1.79-1.65(m,1H),1.45-0.95(m,15H)ppm; HRMS(ESI):calcd.for[C 25 H 34 [N2O5NaS] + ([M+Na)) + ):497.20806,found:497.20776.

[0284] Example 28: Synthesis of compound (R)-Vh

[0285]

[0286] For detailed instructions, please refer to Example 21. The product is a colorless, viscous liquid with a yield of 93%. 1HNMR (400MHz, CDCl3): δ7.81(d,J=8.0Hz,2H),7.36(d,J=8.0Hz,2H),7.20-7.10(m,1H),5.10-4.93(m,2H),4.87-4.45(m,1H),4.21- 3.54(m,1H),2.92-2.61(m,2H),2.44(s,3H),2.32-1.94(m,3H),1.78-1.65(m,1H),1.46-0.93(m,15H)ppm; HRMS(ESI):calcd.for[C 26 H 36 [N2O5NaS] + ([M+Na)) + ):511.22371,found:511.22286.

[0287] Example 29: Synthesis of compound (R,R,R)-VIIa

[0288]

[0289] Under an argon atmosphere, (R,R)-VI (549 mg, 2.16 mmol) and freshly distilled tetrahydrofuran (10 mL) were added to a 100 mL Schlenk flask that had been treated to be anhydrous and oxygen-free. The reaction solution was cooled to -78 °C, and n-butyllithium (1.6 M inhexane, 1.2 mL, 1.92 mmol) was slowly added dropwise. After the addition was complete, the color of the reaction solution changed from colorless to bright yellow. The temperature was then raised to -20 °C, and the reaction was allowed to proceed for 2 hours. A tetrahydrofuran solution of (R)-Va (854 mg, 1.8 mmol) (5 mL) was added to the reaction solution, and the mixture was heated to room temperature and allowed to react overnight. After the reaction was complete, water was added to quench the reaction, followed by extraction with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The resulting pale yellow residue was separated by column chromatography (petroleum ether / ethyl acetate = 4:1) to give a colorless viscous liquid (R,R,R)-VIIa 856 mg. 74% yield. 1 H NMR (400MHz, CDCl3): δ7.49-7.07(m,10H),6.96(s,1H),6.61-6.16(m,1H),5.19-4.76(m,1H),4.36-3.95( m,1H),3.80-3.66(m,1H),3.36-2.69(m,6H),2.55-2.14(m,6H),1.99-1.79(m,1H),1.56-0.12(m,18H)ppm; 31P NMR (202MHz, CDCl3): δ42.89 (s), 42.22 (s) ppm; HRMS (ESI): calcd.for[C 34 H 47 BN2O2P] + ([M+H)) + ):557.34627,found:557.34634.

[0290] Example 30: Synthesis of compound (R,R,R)-VIIb

[0291]

[0292] For detailed instructions, please refer to Example 29. The product is a colorless, viscous liquid with a yield of 83%. 1 H NMR (400MHz, CDCl3): δ7.48-7.05(m,10H),6.60-6.13(m,1H),5.15-4.77(m,1H),4.35-3.90(m,1H), 3.80-3.62(m,1H),3.30-2.67(m,6H),2.53-2.12(m,9H),1.99-1.77(m,1H),1.55-0.11(m,18H)ppm; 31 P NMR (202MHz, CDCl3): δ42.68(s)ppm; HRMS (ESI): calcd.for[C 35 H 49 BN2O2P] + ([M+H)) + ):571.36192,found:571.36126.

[0293] Example 31: Synthesis of compound (R,R,R)-VIIc

[0294]

[0295] For detailed instructions, please refer to Example 29. The product is a white, foamy solid with a yield of 85%. 1 H NMR (400MHz, CDCl3): δ7.54-6.16(m,12H),5.07-4.05(m,3H),3.78-3.66(m,1H),3.15-1.66(m,14H),1.52-0.04(m,18H)ppm; 31 P NMR (162MHz, CDCl3): δ42.59(s)ppm; HRMS (ESI): calcd.for[C 35 H 49BN2O2P] + ([M+H)) + ):571.36192,found:571.36175.

[0296] Example 32: Synthesis of compound (R,R,R)-VIId

[0297]

[0298] For detailed instructions, please refer to Example 29. The product is a white, foamy solid with a yield of 83%. 1 H NMR (400MHz, CDCl3): δ7.50-6.14(m,11H),5.11-4.03(m,3H),3.74-3.60(m,1H),3.15-1.66(m,17H),1.54-0.08(m,18H)ppm; 31 P NMR (162MHz, CDCl3): δ42.89 (s) ppm; HRMS (ESI): calcd.for[C 36 H 51 BN2O2P] + ([M+H)) + ):585.37757,found:585.37702.

[0299] Example 33: Synthesis of compound (R,R,R)-VIIe

[0300]

[0301] For detailed instructions, please refer to Example 29. The product is a white, foamy solid with a yield of 86%. 1 H NMR (400MHz, CDCl3): δ7.52-6.54(m,12H),4.74-3.67(m,3H),3.06-2.02(m,11H),1.43-0.10(m,18H)ppm; 31 P NMR (162MHz, CDCl3): δ44.64(s)ppm; HRMS (ESI): calcd.for[C 33 H 45 BN2O2P] + ([M+H)) + ):543.33062,found:543.32937.

[0302] Example 34: Synthesis of compound (R,R,R)-VIIf

[0303]

[0304] For detailed instructions, please refer to Example 29. The product is a white, foamy solid with a yield of 84%. 1 H NMR (400MHz, CDCl3): δ7.56-6.61(m,11H),4.70-3.60(m,3H),3.09-2.03(m,14H),1.42-0.12(m,18H)ppm; 31 P NMR (162MHz, CDCl3): δ45.58(s)ppm; HRMS (ESI): calcd.for[C 34 H 47 BN2O2P] + ([M+H)) + ):557.34627,found:557.34586.

[0305] Example 35: Synthesis of compound (R,R,R)-VIIg

[0306]

[0307] For detailed instructions, please refer to Example 29. The product is a white, foamy solid with a yield of 92%. 1 H NMR (400MHz, CDCl3): δ7.50-6.51(m,12H),5.03-3.69(m,4H),2.87-1.92(m,11H),1.83-1.66(m,1H),1.53-0.11(m,18H)ppm; 31 P NMR (162MHz, CDCl3): δ42.59(s)ppm; HRMS (ESI): calcd.for[C 34 H 47 BN2O2P] + ([M+H)) + ):557.34627,found:557.34598.

[0308] Example 36: Synthesis of compound (R,R,R)-VIIh

[0309]

[0310] For detailed instructions, please refer to Example 29. The product is a white, foamy solid with a yield of 90%. 1 H NMR (400MHz, CDCl3): δ7.50-6.51(m,11H),5.05-3.61(m,4H),2.87-1.92(m,14H),1.83-1.63(m,1H),1.54-0.11(m,18H)ppm; 31P NMR (162MHz, CDCl3): δ42.87(s)ppm; HRMS (ESI): calcd.for[C 35 H 49 BN2O2P] + ([M+H)) + ):571.36192,found:571.36118.

[0311] Example 37: Synthesis of compound (R,S,S)-VIIa

[0312]

[0313] For detailed instructions, please refer to Example 29. The product is a foamy solid with a yield of 80%. 1 H NMR (400MHz, CDCl3): δ7.52-7.05(m,10H),6.89-6.30(m,2H),5.20-4.69(m,1H), 4.28-3.92(m,1H),3.79-3.67(m,1H),3.38-1.79(m,13H),1.55-0.05(m,18H)ppm; 31 P NMR (162MHz, CDCl3): δ42.30(s)ppm; HRMS (ESI): calcd.for[C 34 H 46 BN2O2NaP] + ([M+Na)) + ):559.32822,found:559.32728.

[0314] Example 38: Synthesis of compound (R,S,S)-VIIc

[0315]

[0316] For detailed instructions, please refer to Example 29. The product is a white, foamy solid with a yield of 85%. 1 H NMR (400MHz, CDCl3): δ7.55-6.52(m,12H),5.09-4.22(m,3H),3.82-3.64(m,1H),3.40-1.60(m,14H),1.57-0.05(m,18H)ppm; 31 P NMR (162MHz, CDCl3): δ42.20(s)ppm; HRMS (ESI): calcd.for[C 35 H 49 BN2O2P] + ([M+H)) +):571.36192,found:571.36127.

[0317] Example 39: Synthesis of compound (R,S,S)-VIIe

[0318]

[0319] For detailed instructions, please refer to Example 29. The product is a white, foamy solid with a yield of 91%. 1 H NMR (400MHz, CDCl3): δ7.52-6.68(m,12H),4.71-3.66(m,3H),3.05-2.06(m,11H),1.40-0.10(m,18H)ppm; 31 P NMR (162MHz, CDCl3): δ45.00 (s) ppm; HRMS (ESI): calcd.for[C 33 H 45 BN2O2P] + ([M+H)) + ):543.33062,found:543.32982.

[0320] Example 40: Synthesis of compound (R,S,S)-VIIg

[0321]

[0322] For detailed instructions, please refer to Example 29. The product is a white, foamy solid with a yield of 97%. 1 H NMR (400MHz, CDCl3): δ7.47-6.52(m,12H),5.02-3.64(m,4H),2.85-1.95(m,11H),1.81-1.67(m,1H),1.51-0.10(m,18H)ppm; 31 P NMR (162MHz, CDCl3): δ42.27(s)ppm; HRMS (ESI): calcd.for[C 34 H 47 BN2O2P] + ([M+H)) + ):557.34627,found:557.34558.

[0323] Example 41: Synthesis of compound (R,R,R)-VIIi

[0324]

[0325] For detailed instructions, please refer to Example 29. The product is a white, foamy solid with a yield of 81%.1 H NMR (400MHz, CDCl3): δ7.52-6.30(m,8H),4.71-3.63(m,3H),3.08-2.01(m,23H),1.41-0.11(m,18H)ppm; 31 P NMR (162MHz, CDCl3): δ44.64(s)ppm; HRMS (ESI): calcd.for[C 37 H 53 BN2O2P] + ([M+H)) + ):584.35317,found:584.35287.

[0326] Example 42: Synthesis of compound (R,R,R)-VIIj

[0327]

[0328] For detailed instructions, please refer to Example 29. The product is a white, foamy solid with a yield of 85%. 1 H NMR (400MHz, CDCl3): δ7.51-6.50(m,12H),4.92-3.61(m,3H),3.15-1.89(m,17H),1.43-0.11(m,18H)ppm; 31 P NMR (162MHz, CDCl3): δ37.86(s)ppm; HRMS (ESI): calcd.for[C 36 H 51 BN2O2P] + ([M+H)) + ):585.37757,found:585.37689.

[0329] Example 43: Synthesis of compound (R,R,R)-Ia

[0330]

[0331] Under an argon atmosphere, compound (R,R,R)-VIIa (256 mg, 0.46 mmol) and freshly distilled dichloromethane (5 mL) were added to a 50 mL Schlenk flask that had been treated to remove gas by freezing and degassing three times. The mixture was then cooled to 0 °C, and trifluoroacetic acid (0.68 mL, 9.2 mmol) and HBF4·Et2O (0.63 mL, 4.6 mmol) were added. The reaction was allowed to proceed at room temperature for 24 h. After the reaction was complete, the solvent was removed under vacuum, and the reaction was quenched in a glove box with degassed saturated sodium bicarbonate solution (resulting in a large number of bubbles). The mixture was extracted with degassed dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was then dried to obtain a colorless oily liquid (R,R,R)-Ia, 181 mg. The yield was 89%. 1 H NMR (400MHz, CDCl3): δ7.27-7.02(m,8H),7.00-6.87(m,3H),6.67(d,J=8.0Hz,1H),3.98(t,J=6.8Hz,1 H),3.68-3.49(m,2H),2.85-2.74(m,2H),2.67-2.16(m,8H),2.04-1.55(m,4H),0.86-0.74(m,6H)ppm; 31 P NMR (162MHz, CDCl3) δ17.72 (s) ppm; HRMS (ESI): calcd.for[C 29 H 36 N2P] + ([M+H)) + ):443.26106,found:443.26070.

[0332] Example 44: Synthesis of compound (R,R,R)-Ib

[0333]

[0334] For detailed instructions, please refer to Example 43. The product is a colorless, oily liquid with a yield of 95%. 1 H NMR (400MHz, CDCl3): δ7.35-6.85 (m, 10H), 6.65 (s, 1H), 3.94 (t, J = 6.8Hz, 1H), 3.67-3.45 (m,2H),2.88-2.71(m,2H),2.69-2.13(m,11H),2.04-1.53(m,4H),0.88-0.71(m,6H)ppm; 31 P NMR(162MHz, CDCl3)δ17.18(s)ppm; HRMS(ESI):calcd.for[C 30 H 38N2P] + ([M+H)) + ):457.27671,found:457.27602.

[0335] Example 45: Synthesis of compound (R,R,R)-Ic

[0336]

[0337] For detailed instructions, please refer to Example 43. The product is a colorless, oily liquid with a yield of 90%. 1 H NMR (400MHz, CDCl3): δ7.39-7.27(m,4H),7.21-7.12(m,3H),7.12-7.03(m,2H ),7.01(d,J=7.6Hz,2H),6.68(d,J=8.0Hz,1H),3.78-3.65(m,1H),3.63-3.55 (m,1H),3.53-3.43(m,1H),2.79(dd,J=13.2,4.0Hz,1H),2.75-2.33(m,8H),2 .13-2.04(m,1H),2.00-1.88(m,2H),1.78-1.62(m,3H),0.95-0.88(m,6H)ppm; 31 P NMR (162MHz, CDCl3): δ16.87(s)ppm; HRMS (ESI): calcd.for[C 30 H 38 N2P] + ([M+H)) + ):457.27671,found:457.27692.

[0338] Example 47: Synthesis of compound (R,R,R)-Id

[0339]

[0340] For detailed instructions, please refer to Example 43. The product is a colorless, oily liquid with a yield of 90%. 1 H NMR (400MHz, CDCl3): δ7.38-6.92(m,10H),6.72-6.64(m,1H),3.77-3.40(m,3H) ,2.82-2.34(m,9H),2.23-1.89(m,6H),1.79-1.61(m,3H),0.94-0.88(m,6H)ppm; 31 P NMR (162MHz, CDCl3): δ16.97(s)ppm; HRMS (ESI): calcd.for[C31 H 40 N2P] + ([M+H)) + ):471.29236,found:471.29174.

[0341] Example 48: Synthesis of compound (R,R,R)-Ie

[0342]

[0343] For detailed instructions, please refer to Example 43. The product is a colorless, oily liquid with a yield of 80%. 1 H NMR (400MHz, CDCl3): δ7.37-7.00(m,11H),6.66(d,J=7.6Hz,1H),4.17(t,J=7.6Hz,1H),3.79-3.66(m,2H),3.17 -3.07(m,1H),2.92-2.81(m,1H),2.75-2.55(m,2H),2.49-2.34(m,4H),2.02-1.76(m,4H),1.21-1.14(m,6H)ppm; 31 P NMR (162MHz, CDCl3): δ17.50(s)ppm; HRMS (ESI): calcd.for[C 28 H 34 N2P] + ([M+H)) + ):429.24541,found:429.24479.

[0344] Example 49: Synthesis of compound (R,R,R)-If

[0345]

[0346] For detailed instructions, please refer to Example 43. The product is a colorless, oily liquid with a yield of 89%. 1 H NMR (400MHz, CDCl3): δ7.37-6.99(m,10H),6.68-6.63(m,1H),4.15(t,J=7.6Hz,1H),3.74-3.61(m,2H),3.1 7-3.06(m,1H),2.91-2.78(m,1H),2.75-2.32(m,6H),2.21(s,3H),2.04-1.75(m,4H),1.21-1.13(m,6H)ppm; 31 P NMR (162MHz, CDCl3): δ17.33(s)ppm; HRMS (ESI): calcd.for[C 29H 36 N2P] + ([M+H)) + ):443.26106,found:443.26076.

[0347] Example 50: Synthesis of compound (R,R,R)-Ig

[0348]

[0349] For detailed instructions, please refer to Example 43. The product is a colorless, oily liquid with a yield of 95%. 1 HNMR (400MHz, CDCl3): δ7.36-7.30(m,4H),7.25-7.05(m,5H),7.01(d,J=7.6Hz,2H),6.63(d,J=8.0Hz,1H),3.86-3.67(m,3H),3.11 -2.99(m,1H),2.85-2.57(m,4H),2.49-2.32(m,3H),2.21-2.10(m,1H),2.06-1.88(m,3H),1.80-1.62(m,2H),1.21-1.13(m,6H)ppm; 31 P NMR (162MHz, CDCl3): δ17.60(s)ppm; HRMS (ESI): calcd.for[C 29 H 36 N2P] + ([M+H)) + ):443.26106,found:443.26075.

[0350] Example 51: Synthesis of compound (R,R,R)-Ih

[0351]

[0352] For detailed instructions, please refer to Example 43. The product is a colorless, oily liquid with a yield of 88%. 1 HNMR (400MHz, CDCl3): δ7.38-6.99(m,10H),6.69-6.63(m,1H),3.85-3.67(m,3H),3.10-2.96(m,1H),2.88-2. 56(m,4H),2.50-2.33(m,3H),2.24-2.09(m,4H),2.05-1.88(m,3H),1.80-1.63(m,2H),1.20-1.11(m,6H)ppm; 31P NMR (162MHz, CDCl3): δ17.26(s)ppm; HRMS (ESI): calcd.for[C 30 H 38 N2P] + ([M+H)) + ):457.27671,found:457.27586.

[0353] Example 52: Synthesis of compound (R,S,S)-Ia

[0354]

[0355] For detailed instructions, please refer to Example 43. The product is a colorless, oily liquid with a yield of 84%. 1 H NMR (400MHz, CDCl3): δ7.32-6.86(m,11H),6.59(d,J=7.6Hz,1H),4.00(t,J=7.2Hz,1H),3.71 -3.57(m,2H),2.86-2.72(m,2H),2.69-2.21(m,8H),2.05-1.62(m,4H),0.93-0.81(m,6H)ppm; 31 P NMR (162MHz, CDCl3): δ17.51(s)ppm; HRMS (ESI): calcd.for[C 29 H 36 N2P] + ([M+H)) + ):443.26106,found:443.26018.

[0356] Example 53: Synthesis of compound (R,S,S)-Ic

[0357]

[0358] For detailed instructions, please refer to Example 43. The product is a colorless, oily liquid with a yield of 72%. 1 H NMR (400MHz, CDCl3): δ7.29-7.24(m,4H),7.16-7.06(m,3H),7.05-6.98(m,2H),6.93(d,J=7.6Hz,2H),6.56(d,J=8.0Hz,1H),3.81- 3.50(m,3H),2.82-2.17(m,10H),2.09-2.05(m,1H),1.94-1.82(m,2H),1.78-1.70(m,1H),1.67-1.52(m,2H),0.94-0.83(m,6H)ppm; 31P NMR (162MHz, CDCl3): δ17.40(s)ppm; HRMS (ESI): calcd.for[C 30 H 38 N2P] + ([M+H)) + ):457.27671,found:457.27706.

[0359] Example 54: Synthesis of compound (R,S,S)-Ie

[0360]

[0361] For detailed instructions, please refer to Example 43. The product is a colorless, oily liquid with a yield of 90%. 1 HNMR (400MHz, CDCl3): δ7.36-6.97(m,11H),6.68(d,J=8.0Hz,1H),4.13(t,J=7.6Hz,1H),3.81-3.65(m,2H),3.16 -3.06(m,1H),2.90-2.83(m,1H),2.77-2.55(m,2H),2.48-2.33(m,4H),2.05-1.74(m,4H),1.23-1.11(m,6H)ppm; 31 P NMR (162MHz, CDCl3): δ17.13(s)ppm; HRMS (ESI): calcd.for[C 28 H 34 N2P] + ([M+H)) + ):429.24541,found:429.24463.

[0362] Example 55: Synthesis of compound (R,S,S)-Ig

[0363]

[0364] For detailed instructions, please refer to Example 43. The product is a colorless, oily liquid with a yield of 91%. 1 H NMR (400MHz, CDCl3): δ7.39-7.00(m,11H),6.66(d,J=8.0Hz,1H),3.89-3.63(m,3H),3.14-2.97(m,1H) ),2.84-2.57(m,4H),2.47-2.31(m,3H),2.23-1.88(m,4H),1.81-1.60(m,2H),1.21-1.12(m,6H)ppm; 31P NMR (162MHz, CDCl3): δ16.94(s)ppm; HRMS (ESI): calcd.for[C 29 H 36 N2P] + ([M+H)) + ):443.26106,found:443.26088.

[0365] Example 56: Synthesis of compound (R,R,R)-Ii

[0366]

[0367] For detailed instructions, please refer to Example 43. The product is a colorless, oily liquid with a yield of 88%. 1 H NMR (400MHz, CDCl3): δ7.37-6.56(m,8H),4.11(t,J=7.6Hz,1H),3.70-3.58(m,2H),3.14-3. 03(m,1H),2.91-2.83(m,1H),2.74-2.58(m,2H),2.49-1.79(m,20H),1.23-1.11(m,6H)ppm; 31 P NMR (162MHz, CDCl3): δ16.64(s)ppm; HRMS (ESI): calcd.for[C 32 H 42 N2P] + ([M+H)) + ):485.30801,found:485.30761.

[0368] Example 57: Synthesis of compound (R,R,R)-Ij

[0369]

[0370] For detailed instructions, please refer to Example 43. The product is a colorless, oily liquid with a yield of 89%. 1 HNMR (400MHz, CDCl3): δ7.32-6.99 (m, 11H), 6.61 (d, J = 7.6Hz, 1H), 4.03 (t, J=7.2Hz,1H),3.21-2.15(m,14H),2.05-1.62(m,6H),0.99-0.80(m,6H)ppm; 31 P NMR (162MHz, CDCl3): δ1.05(s)ppm; HRMS (ESI): calcd.for[C 31 H 40 N2P] +([M+H)) + ):471.29236,found:471.29128.

[0371] Example 58: Synthesis of compound (R,R,R)-VIIIa

[0372]

[0373] Inside a glove box, manganese pentacarbonyl bromide (93 mg, 0.34 mmol), (R,R,R)-Ia (155 mg, 0.35 mmol), and degassed toluene (5 mL) were added to a 50 mL dry Schlenk tube. The reaction mixture was heated to 80 °C and reacted for 16 h under an argon atmosphere, resulting in a brownish-red solution. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, washed with toluene, and the filtrate was dried under a cold trap. 2-3 drops of toluene were added to dissolve the solid, and then n-hexane was added. A large amount of solid precipitated, which was filtered to obtain an orange-yellow solid powder (R,R,R)-VIIIa, 152 mg, yield 71%. 1 H NMR(400MHz, CDCl3):7.56-6.93(m,12H),4.82-4.67(m,1H),4.37-4.22(m,1H),3.84-3.6 9(m,1H),3.40-2.67(m,7H),2.65-2.06(m,6H),1.88-1.67(m,1H),1.07-0.82(m,6H)ppm; 31 P NMR(162MHz, CDCl3)δ125.49(s)ppm; HRMS(ESI):calcd.for[C 31 H 35 N2O2PMn] + ([M-Br)) + ):553.18112,found:553.18072.

[0374] Example 59: Synthesis of compound (R,R,R)-VIIIb

[0375]

[0376] For detailed instructions, please refer to Example 58. Orange-yellow solid, yield 83%. 1 HNMR(400MHz, CDCl3):7.58-6.87(m,11H),4.83-2.01(m,19H),1.88-1.67(m,1H),1.07-0.82(m,6H)ppm; 31P NMR(162MHz, CDCl3)δ127.34(s)ppm; HRMS(ESI):calcd.for[C 32 H 37 N2O2PMn] + ([M-Br)) + ):567.19677,found:567.19547.

[0377] Example 60: Synthesis of compound (R,R,R)-VIIIc

[0378]

[0379] For detailed instructions, please refer to Example 58. Orange-yellow solid, yield 70%. 1 H NMR (400MHz, CDCl3): δ7.76-6.81(m,12H),4.97-4.64(m,1H),4.03-3.58(m,2H),3.49-1.87(m,13H),1.81-0.72(m,9H)ppm; 31 P NMR (162MHz, CDCl3): δ122.22(s)ppm; HRMS (ESI): calcd for[C 32 H 37 N2O2PMn] + ([M-Br)) + ):567.19677,found:567.19615.

[0380] Example 61: Synthesis of compound (R,R,R)-VIIId

[0381]

[0382] For detailed instructions, please refer to Example 58. Orange-yellow solid, yield 70%. 1 H NMR (400MHz, CDCl3): δ7.68-6.85(m,11H),4.88-1.90(m,19H),1.81-0.74(m,9H)ppm; 31 P NMR (162MHz, CDCl3): δ120.59(s)ppm; HRMS (ESI): calcd for[C 33 H 39 N2O2PMn] + ([M-Br)) + ):581.21242,found:581.21186.

[0383] Example 62: Synthesis of compound (R,R,R)-VIIIe

[0384]

[0385] For detailed instructions, please refer to Example 58. Orange-yellow solid, yield 87%. 1 H NMR (400MHz, CDCl3): δ7.63-6.86(m,12H), 4.90-1.88(m,14H), 1.79-0.74(m,7H)ppm; 31 P NMR (162MHz, CDCl3): δ123.64(s)ppm; HRMS (ESI): calcd for[C 30 H 33 N2O2PMn] + ([M-Br)) + ):539.16547,found:539.16487.

[0386] Example 63: Synthesis of compound (R,R,R)-VIIIf

[0387]

[0388] For detailed instructions, please refer to Example 58. Orange-yellow solid, yield 79%. 1 HNMR (400MHz, CDCl3): δ7.66-6.84(m,11H),4.83-1.87(m,17H),1.81-0.73(m,7H)ppm; 31 P NMR(162MHz, CDCl3): δ122.68(s)ppm; HRMS(ESI):calcd for[C 31 H 35 N2O2PMn] + ([M-Br)) + ):553.18112,found:553.18073.

[0389] Example 64: Synthesis of compound (R,R,R)-VIIIg

[0390]

[0391] For detailed instructions, please refer to Example 58. Orange-yellow solid, yield 89%. 1 HNMR (400MHz, CDCl3): δ7.71-6.88(m,12H),4.78-1.88(m,14H),1.80-0.79(m,9H)ppm; 31P NMR(162MHz, CDCl3): δ121.33(s)ppm; HRMS(ESI):calcd for[C 31 H 35 N2O2PMn] + ([M-Br)) + ):553.18112,found:553.18048.

[0392] Example 65: Synthesis of compound (R,R,R)-VIIIh

[0393]

[0394] For detailed instructions, please refer to Example 58. Orange-yellow solid, yield 80%. 1 HNMR (400MHz, CDCl3): δ7.68-6.86(m,11H),4.88-1.90(m,17H),1.81-0.88(m,9H)ppm; 31 P NMR(162MHz, CDCl3): δ122.39(s)ppm; HRMS(ESI):calcd for[C 32 H 37 N2O2PMn] + ([M-Br)) + ):567.19677,found:567.19623.

[0395] Example 66: Synthesis of compound (R,S,S)-VIIIa

[0396]

[0397] For detailed instructions, please refer to Example 58. Yellow solid, yield 70%. 1 H NMR (400MHz, CDCl3): δ7.79-6.54(m,12H),5.43-4.23(m,1H),4.06-3.31(m,3H),3.17-1.93(m,11H),1.81-0.50(m,8H)ppm; 31 P NMR (162MHz, CDCl3): δ125.96 (s) ppm; HRMS (ESI): calcd.for[C 31 H 35 N2O2PMn] + ([M-Br)) + ):553.18112,found:553.18044.

[0398] Example 67: Synthesis of compound (R,S,S)-VIIIc

[0399]

[0400] For detailed instructions, please refer to Example 58. Yellow solid, yield 66%. 1 H NMR (400MHz, CDCl3): δ7.90-6.46(m,12H)4.23-1.56(m,16H),1.43-0.69(m,9H)ppm; 31 P NMR(162MHz, CDCl3): δ124.02(s)ppm; HRMS(ESI)calcd.for[C 32 H 37 N2O2PMn] + ([M-Br)) + ):567.19677,found:567.19666.

[0401] Example 68: Synthesis of compound (R,S,S)-VIIIe

[0402]

[0403] For detailed instructions, please refer to Example 58. Yellow solid, yield 90%. 1 H NMR (400MHz, CDCl3): δ7.84-6.57(m,12H)4.36-1.59(m,14H),1.48-0.76(m,7H)ppm; 31 P NMR(162MHz, CDCl3): δ123.63(s)ppm; HRMS(ESI)calcd.for[C 30 H 33 N2O2PMn] + ([M-Br)) + ):539.16547,found:539.16458.

[0404] Example 69: Synthesis of compound (R,S,S)-VIIIg

[0405]

[0406] For detailed instructions, please refer to Example 58. Yellow solid, yield 94%. 1 H NMR (400MHz, CDCl3): δ7.85-6.54(m,12H)4.36-1.67(m,14H),1.46-0.73(m,9H)ppm; 31P NMR(162MHz, CDCl3): δ126.37(s)ppm; HRMS(ESI)calcd.for[C 31 H 35 N2O2PMn] + ([M-Br)) + ):553.18112,found:553.18065.

[0407] Example 70: Synthesis of compound (R,R,R)-VIIIi

[0408]

[0409] For detailed instructions, please refer to Example 58. Yellow solid, yield 76%. 1 H NMR (400MHz, CDCl3): δ7.65-6.54(m,8H)4.65-1.67(m,27H),1.10-0.73(m,6H)ppm; 31 P NMR(162MHz, CDCl3): δ123.46(s)ppm; HRMS(ESI)calcd.for[C 34 H 41 N2O2PMn] + ([M-Br)) + ):595.22807,found:595.22764.

[0410] Example 71: Synthesis of compound (R,R,R)-VIIIj

[0411]

[0412] For detailed instructions, please refer to Example 58. Yellow solid, yield 81%. 1 H NMR (400MHz, CDCl3): δ7.44-6.59(m,12H)4.56-2.10(m,14H),2.03-1.58(m,7H),1.44-0.95(m,6H)ppm; 31 P NMR(162MHz, CDCl3): δ110.83(s)ppm; HRMS(ESI)calcd.for[C 33 H 39 N2O2PMn] + ([M-Br)) + ):581.21242,found:581.21173.

[0413] Example 72: Synthesis of (S,S,S)-Ia and (R,R,R)-VIIIa

[0414]

[0415] Using (S)-IIa as a starting material, and following the synthetic routes of (R,R,R)-Ia and (R,R,R)-VIIIa, compounds (S,S,S)-Ia and (S,S,S)-VIIIa can be prepared.

[0416] Asymmetric catalytic hydrogenation reaction

[0417] Example 73: Asymmetric hydrogenation of acetophenone catalyzed by manganese complex (R,S,S)-VIIIe (parts per thousand catalyst)

[0418]

[0419] In a glove box, potassium tert-butoxide (2.2 mg, 0.02 mmol), a methanol solution of manganese complex (R,S,S)-VIIIe (0.001 mol / L, 1 mL, 0.001 mmol), and acetophenone (120 mg, 1 mmol) were added to a 125 mL autoclave. The autoclave was sealed and removed from the glove box, then purged with hydrogen at 50 bar. The reaction mixture was stirred at 25-30 °C for 16 hours. Excess hydrogen was slowly released. The reaction solution was filtered through silica gel to remove metals and alkalis. The conversion rate of acetophenone was determined to be >99% by gas chromatography, and the ee value of the product phenethyl alcohol was 95%. Gas chromatography conditions: GC (Supelco β-DEX). TM 120, carrier gas, N2 (flowrate1 mL / min); injection temp, 250℃; oven temperature, 120℃; detectortemperature, 300℃); t R =14.8min (minor); t R =16.0 min (major). The conversion rate of acetophenone (%) = [(S)-phenethyl alcohol peak area + (R)-phenethyl alcohol peak area] / [acetophenone peak area + (S)-phenethyl alcohol peak area + (R)-phenethyl alcohol peak area] × 100%. The absolute configuration of phenethyl alcohol was confirmed by optical rotation comparison with the standard.

[0420] Example 74: Asymmetric hydrogenation of acetophenone catalyzed by manganese complex (R,S,S)-VIIIe (parts 1 / 10,000 catalyst dosage)

[0421]

[0422] In a glove box, potassium tert-butoxide (22.4 mg, 0.2 mmol), a methanol solution of manganese complex (R,S,S)-VIIIe (0.001 mol / L, 1 mL, 0.001 mmol), anhydrous methanol (4 mL), and acetophenone (1.20 g, 10 mmol) were added to a 125 mL autoclave. The autoclave was sealed and removed from the glove box, then purged with hydrogen at 50 bar. The reaction mixture was stirred at 25–30 °C for 48 hours. Excess hydrogen was slowly released. The reaction solution was filtered through silica gel to remove metals and alkalis. The conversion rate of acetophenone was determined to be >99% by gas chromatography, and the ee value of the product phenethyl alcohol was 94%. Gas chromatography conditions: GC (Supelco β-DEX). TM 120, carrier gas, N2 (flow rate 1 mL / min); injection temp, 250℃; oven temperature, 120℃; detector temperature, 300℃); t R =14.8min (minor); t R =16.0 min (major). The conversion rate of acetophenone (%) = [(S)-phenethyl alcohol peak area + (R)-phenethyl alcohol peak area] / [acetophenone peak area + (S)-phenethyl alcohol peak area + (R)-phenethyl alcohol peak area] × 100%. The absolute configuration of phenethyl alcohol was confirmed by optical rotation comparison with the standard.

[0423] Example 75: Asymmetric hydrogenation of acetophenone catalyzed by manganese complex (R,S,S)-VIIIe (catalyst dosage 0.20001%)

[0424]

[0425] In a glove box, potassium tert-butoxide (44.8 mg, 0.4 mmol), a methanol solution of manganese complex (R,S,S)-VIIIe (0.001 mol / L, 1 mL, 0.001 mmol), anhydrous methanol (6 mL), and acetophenone (2.40 g, 20 mmol) were added to a 125 mL autoclave. The autoclave was sealed and removed from the glove box, and hydrogen gas was introduced at 50 bar. The reaction mixture was stirred at 50 °C for 48 hours. Excess hydrogen gas was slowly released. The reaction solution was filtered through silica gel to remove metals and alkalis. The conversion rate of acetophenone was determined to be 96% by gas chromatography, and the ee value of the product phenethyl alcohol was 92%. Gas chromatography conditions: GC (Supelco β-DEX). TM120, carrier gas, N2 (flow rate 1 mL / min); injection temp, 250℃; oven temperature, 120℃; detector temperature, 300℃); t R =14.8min (minor); t R =16.0 min (major). The conversion rate of acetophenone (%) = [(S)-phenethyl alcohol peak area + (R)-phenethyl alcohol peak area] / [acetophenone peak area + (S)-phenethyl alcohol peak area + (R)-phenethyl alcohol peak area] × 100%. The absolute configuration of phenethyl alcohol was confirmed by optical rotation comparison with the standard.

[0426] Comparative Example 1: Asymmetric hydrogenation of acetophenone catalyzed by a non-fused-ring manganese complex (comparative experiment)

[0427]

[0428] Using non-ringed manganese complexes Mn1 and Mn2 as catalysts, under the reaction conditions of Example 74, the ee value of the obtained phenylethanol was significantly lower than that of the present invention.

[0429] Example 76: Asymmetric hydrogenation of conjugated enone XI catalyzed by manganese complex (R,R,R)-VIIIa

[0430] In a glove box, manganese complex (R,R,R)-VIIIa (3.2 mg, 0.005 mmol) was added sequentially to a 10 mL hydrogenation flask. t Bu (1.2 mg, 0.01 mmol), MeOH (1 mL), and XI (0.5 mmol). The reaction flask was placed in a 125 mL autoclave, sealed, and removed from the glove box. The autoclave was purged with hydrogen three times, then purged with 50 bar hydrogen gas, and the reaction was stirred at room temperature for 16 hours. After the reaction was complete, the hydrogen gas in the autoclave was slowly released. The reaction solution was purified by column chromatography to obtain the separated yield. The ee value was determined by HPLC.

[0431]

[0432] Example 77: Asymmetric hydrogenation of conjugated enone XI catalyzed by manganese complex (S,S,S)-VIIIa

[0433]

[0434] In a glove box, manganese complex (R,R,R)-VIIIa (3.2 mg, 0.005 mmol) was added sequentially to a 10 mL hydrogenation flask. tBu (1.2 mg, 0.01 mmol), MeOH (1 mL), and substrate (0.5 mmol) were added. The reaction flask was placed in a 125 mL autoclave, sealed, and removed from the glove box. After purging the autoclave with hydrogen three times, it was purged with 50 bar of hydrogen and stirred at room temperature for 16 hours. After the reaction was complete, the hydrogen gas in the autoclave was slowly released. The reaction solution was purified by column chromatography, yielding a separation yield of 98% and an ee value of 92% as determined by HPLC.

[0435] Comparative Example 2: Asymmetric hydrogenation of XI catalyzed by other manganese complexes

[0436]

[0437] Using non-ringed manganese complexes Mn3 and Mn4 as catalysts, under the reaction conditions of Example 76, the ee value of the obtained allyl alcohol was significantly lower than that of the present invention.

[0438] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A chiral amino-pyridine-phosphine tridentate ligand of Formula I: wherein * represents a chiral carbon atom, which is either R or S configuration; n is an integer from 0 to 2; R 1 is -CH-R'R", wherein R' is selected from the group consisting of H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C8cycloalkyl; and R" is selected from the group consisting of substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C8cycloalkyl; said substitution means that one or more hydrogens on the group are replaced by a group individually selected from the group consisting of phenyl, substituted phenyl, wherein said substitution means that said phenyl is substituted by one or more (e.g., 1, 2, 3, 4, or 5) groups individually selected from the group consisting of halogen, C1-C6alkyl, halogenated C1-C6alkyl, C1-C6alkoxy; and 10 is -CH-R'R", wherein R' is selected from the group consisting of H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C8cycloalkyl; and R" is selected from the group consisting of substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C8cycloalkyl; said substitution means that one or more hydrogens on the group are replaced by a group individually selected from the group consisting of phenyl, substituted phenyl, wherein said substitution means that said phenyl is substituted by one or more (e.g., 1, 2, 3, 4, or 5) groups individually selected from the group consisting of halogen, C1-C6alkyl, halogenated C1-C6alkyl, C1-C6alkoxy; and 10 is -CH-R'R", wherein R' is selected from the group consisting of H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C8cycloalkyl; and R" is selected from the group consisting of substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C8c R 2 H, halogen, C1-C 10 Alkyl, C1-C 10 Alkoxy, 4-10 membered heterocyclic alkyl groups containing 1-3 heteroatoms independently selected from N, O and S, substituted or unsubstituted C6-C 10 Aryl; wherein the substitution refers to the substitution of one or more hydrogen atoms on the group by groups independently selected from the group consisting of: halogens, C1-C2 groups, etc. 10 Alkyl, C1-C 10 Alkoxy; R 3 Each is independently either substituted or unsubstituted C6-C. 10 Aryl, substituted or unsubstituted benzyl, wherein the substitution refers to one or more hydrogen atoms on the group being replaced by groups independently selected from the group consisting of C1 to C2. 10 Alkyl, C3-C 10 cycloalkyl or C1-C 10 Alkoxy; wherein and denotes the relative configuration of the C atom, when is , is when is , is 2. The ligand of claim 1, wherein The ligands are selected from the following group:

3. A method of preparing the ligand of claim 1, characterized by, Includes the following steps: (1) the compound of formula II is subjected to a reductive amination reaction in the presence of a reducing agent with a compound of formula 0 followed by an upper protecting group reaction with di-tert-butyl dicarbonate to give a compound of formula III; (2) Compound III undergoes oxidation in the presence of an oxidizing agent, followed by rearrangement with carboxylic anhydride, and finally hydrolysis in the presence of a base to obtain compound IV. (3) In the presence of a base, compound IV reacts with the acylating agent RSO2Cl to obtain compound V; (4) In the presence of a base, compound V undergoes a nucleophilic substitution reaction with compound VI to give compound VII; (5) In the presence of trifluoroacetic acid and tetrafluoroboric acid, the compound of formula VII undergoes a deprotection reaction to obtain the compound shown in formula I; in, R' and R" are as described in claim 1; R is selected from the group consisting of C 1-8 alkyl, C 1-6 alkyl-substituted or unsubstituted phenyl.

4. An intermediate for the preparation of a ligand of formula I, characterized in that ###00001### I The intermediates are selected from the following group: wherein *, n, R, R 1 , R 2 and R 3 are as described in claim 1.

5. A metal complex represented by Formula VIII; Metal(L)(CO)2X VIII in, X is a chloride ion or a bromide ion; L is wherein *, n, R 1 , R 2 and R 3 are as described in claim 1 ; Metal refers to metal ions.

6. The metal complex of claim 5, wherein, The complexes are selected from the following group:

7. A method of preparing a manganese complex of formula VIII-a, characterized in that, Includes the following steps Under the protection of an inert gas, the ligand shown in Formula I reacts with a manganese metal precursor in an inert solvent to obtain the manganese complex shown in Formula VIII-a. The manganese metal precursors mentioned above are Mn(CO)5Br and Mn(CO)5Cl; *, R 1 2 3 and n are as described in claim 1.​​ 8. The method of claim 7, wherein, The molar ratio of the manganese metal precursor to the ligand shown in Formula I is 1:(1-2), preferably 1:(1-1.3), and more preferably 1:

1.

9. A method for asymmetric catalytic hydrogenation of a compound of formula IX, characterized in that, Includes the following steps: (a) In an organic solvent, under a hydrogen atmosphere, and in the presence of a base, the compound of formula IX is reduced to the compound of formula X by the catalysis of the manganese complex shown in formula VIII-a. In the formula, R 4 substituted or unsubstituted C6-C10aryl; or 10 substituted or unsubstituted C6-C10aryl; or 10 substituted or unsubstituted C6-C10aryl; or R 5 substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C8cycloalkyl; wherein said substitution is one or more hydrogens on a group replaced by a member selected from the group consisting of halogen, hydroxy, benzyloxy, C1-C6alkyl, halogenated C1-C6alkyl, C1-C6alkoxy, C6-C10aryl, 4-10 membered heteroaryl containing 1-3 heteroatoms each independently selected from N, O, and S; and 10 substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C8cycloalkyl; wherein said substitution is one or more hydrogens on a group replaced by a member selected from the group consisting of halogen, hydroxy, benzyloxy, C1-C6alkyl, halogenated C1-C6alkyl, C1-C6alkoxy, C6-C 10 substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C8cycloalkyl; wherein said substitution is one or more hydrogens on a group replaced by a member selected from the group consisting of halogen, hydroxy, benzyloxy, C1-C6alkyl, halogenated C1-C6alkyl, C1-C6alkoxy, C6-C Wherein, the compound of formula VIII-a is Mn(L)(CO)2X; L and X are as described in claim 5.

10. A method for asymmetric catalytic hydrogenation of a compound represented by formula XI, characterized in that, Includes the following steps: (c) In an organic solvent, under a hydrogen atmosphere, and in the presence of a base, the compound of formula XI is reduced to the compound of formula XII by the catalysis of the manganese complex shown in formula VIII-a. In the formula, R 6 , R 7 and R 8 are each independently selected from the group consisting of substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C6-C10aryl, and substituted or unsubstituted 4-10 membered heteroaryl containing 1-3 heteroatoms each independently selected from N, O, and S; wherein said substitution is one or more hydrogens on a group replaced with a group selected from the group consisting of hydroxy, t-butyldimethylsiloxy, halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, cyano, and oxo; 10 R 10 R 10 R 1-6 R 1-6 R 1-6 R 2-6 R Wherein, the compound of formula VIII-a is Mn(L)(CO)2X; L and X are as described in claim 5.

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