Preparation method of chiral alcohol compound

Abstract

The invention discloses a preparation method of a chiral alcohol compound. The method comprises the following steps: reacting an achiral alcohol compound in the presence of a titanium catalyst, a ligand and alkali in a solvent under illumination and anhydrous conditions to obtain the chiral alcohol compound. According to the method, only a titanium catalyst and a chiral ligand need to be added, no additional oxidizing agent or reducing agent needs to be added, a series of achiral alcohols can be smoothly synthesized into the chiral alcohols through deracemization under photocatalysis only through one-step reaction, and the reaction can well control the stereoselectivity of the reaction.

Description

Technical Field

[0001] The invention relates to a method for preparing chiral alcohol compounds. Background Art

[0002] Chiral alcohols are a common and important structure in organic matter. The synthesis of chiral alcohol compounds has important research significance in the synthesis of medicines, pesticides, natural products and chiral reagents. At present, there are two main strategies for the synthesis of chiral alcohol compounds: First, asymmetric transformation of prochiral compounds, such as asymmetric reduction of ketones, stereoselective addition of nucleophiles to aldehydes, asymmetric epoxide opening, etc. Although this type of method has been widely studied, there are still problems such as limited substrate applicability, the need for equivalent chiral reagents, and difficulty in synthesizing challenging chiral tertiary alcohols; second, kinetic resolution of racemic alcohols, or dynamic kinetic resolution, is usually carried out under enzyme catalysis. This method also has significant disadvantages, such as in kinetic resolution, half of the alcohol will be converted into other products, that is, the theoretical product is less than 50%; dynamic kinetic resolution overcomes the limitation of theoretical yield by mutual conversion between two isomers, but it is usually very difficult to find a racemization reagent compatible with enzymes. In addition, the resolution method is also limited to the synthesis of chiral secondary alcohols.

[0003] The deracemization reaction synthesizes chiral alcohols, that is, through the breaking and regeneration of chemical bonds within the alcohol molecule, the enrichment of a single chiral alcohol is directly achieved from the racemic alcohol. This method is simple in concept and has a unique charm in synthesis. Compared with the above two methods for constructing chiral alcohols, its advantages are: there is no need to construct an achiral precursor of the alcohol, and the conversion of racemic alcohol to chiral alcohol can be directly achieved; and in theory, a 100% yield can be achieved without causing waste of raw materials; at the same time, the operation is simple, the conditions are mild, and it can be achieved under catalytic amounts of chiral reagents. At the same time, the smooth implementation of this process also faces huge challenges, and it is necessary to overcome both thermodynamic and kinetic difficulties. In 2021, Hu Xile's research group used a tandem redox strategy to achieve the deracemization of benzyl alcohol substrates under the joint action of two mutually compatible achiral dehydrogenation photocatalysts Ni-CdS and Noyori asymmetric hydrogenation catalysts under photocatalysis and the addition of hydrogen as a reducing agent. Summary of the invention

[0004] The technical problem to be solved by the present invention is that the preparation process of chiral alcohol compounds in the prior art is single. To this end, the present invention provides a new preparation method of chiral alcohol compounds. The method only requires the addition of a titanium catalyst and a chiral ligand, and does not require the addition of any additional oxidant or reductant. A series of achiral alcohols can be deracemized and synthesized into chiral alcohols in a single step under photocatalysis. The reaction can well control the stereoselectivity of the reaction.

[0005] The present invention provides a method for preparing a chiral alcohol compound, which comprises the following steps: in a solvent, under light and anhydrous conditions, reacting a non-chiral alcohol compound in the presence of a titanium catalyst, a ligand and a base to obtain a chiral alcohol compound;

[0006] The preparation method is the following method 1, method 2 or method 3:

[0007] Method 1: The achiral alcohol compound is a compound as shown in Formula I, and the chiral alcohol compound is a compound as shown in Formula I-1, a compound as shown in Formula I-2, a compound as shown in Formula I-3, or a compound as shown in Formula I-4;

[0008]

[0009] Method 2: The achiral alcohol compound is a compound as shown in formula II, and the chiral alcohol compound is a compound as shown in formula II-1 or a compound as shown in formula II-2;

[0010]

[0011] Method 3: The achiral alcohol compound is a compound of formula III, and the chiral alcohol compound is a compound of formula III-1 or a compound of formula III-2;

[0012]

[0013] Wherein, Ring A is a 4-20-membered cycloalkyl, a 4-10-membered heterocycloalkyl or a 6-10-membered heteroaryl; the heteroatoms in the 4-10-membered heterocycloalkyl are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 6-10-membered heteroaryl are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0014] Ring B is a 4-20 membered heterocycloalkyl group; the heteroatoms in the 4-20 membered heterocycloalkyl group are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0015] R 1 is unsubstituted or one or more R 1-0 Substituted C1-C6 alkyl, unsubstituted or one or more R 1-1 substituted 6-10 membered aryl, or unsubstituted or one or more R 1-2 A substituted 6-10 membered heteroaryl group, wherein the heteroatoms in the 6-10 membered heteroaryl group are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0016] R 2 is hydrogen or unsubstituted or one or more R 2-1 Substituted C1-C6 alkyl;

[0017] R 3 and R 4 Each independently is unsubstituted or one or more R 3-1 Substituted 6-10 membered aryl;

[0018] R 5 is an amino protecting group;

[0019] R 6 is hydrogen, unsubstituted or one or more R 6-1 Substituted C1-C6 alkyl or unsubstituted or one or more R 6-2 Substituted 6-10 membered aryl;

[0020] R 7 and R 8 is unsubstituted or one or more R 8-1 Substituted C1-C6 alkyl, unsubstituted or one or more R 8-2 A substituted 6-10 membered aryl group, or an amino protecting group;

[0021] m and n are each independently 0, 1, 2 or 3;

[0022] R 1-0 , R 1-1 , R 1-2 , R 2-1 , R 3-1 , R 6-1 , R 6-2 , R 8-1 and R 8-2 Each independently is halogen, unsubstituted or one or more R 1-1-1 Substituted C1-C6 alkyl, unsubstituted or one or more R 1-1-2 Substituted C1-C6 alkoxy, unsubstituted or one or more R 1-1-3 Substituted C1-C6 alkylthio;

[0023] R 1-1-1 , R 1-1-2 and R 1-1-3 are each independently a halogen;

[0024] The titanium catalyst is one or more of titanium tetrachloride, titanium tetrabromide, tetraisopropoxytitanium and bis(cyclopentadienyl)titanium dichloride (TiCp2Cl2);

[0025] The ligand is a chiral bisoxazoline ligand,

[0026] The wavelength of the light is 360-400nm.

[0027] In one embodiment of the present invention, some groups are defined as follows, and undefined groups are the same as described above (hereinafter referred to as "in one embodiment"):

[0028] In a certain embodiment, each of the C1-C6 alkyl groups may independently be a C1-C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or ethyl.

[0029] In a certain embodiment, each of the C1-C6 alkoxy groups can independently be a C1-C4 alkoxy group, such as a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, a sec-butoxy group or a tert-butoxy group, preferably a methoxy group.

[0030] In a certain embodiment, each of the C1-C6 alkylthio groups may independently be a C1-C4 alkylthio group, such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio or tert-butylthio, preferably methylthio.

[0031] In a certain embodiment, each of the halogens may be F, Cl, Br or I, preferably F, Cl or Br.

[0032] In one embodiment, each of the 6-10 membered aryl groups may be phenyl or naphthyl.

[0033] In a certain embodiment, each of the 6-10 membered heteroaryl groups is a 9-10 membered heteroaryl group, the heteroatom is selected from one of N, O and S, and the number of the heteroatom is 1, such as phenylpropyloxyhexyl, benzofuranyl or benzothiopheneyl.

[0034] In a certain embodiment, each of the 4-20-membered cycloalkyl groups is a 4-15-membered cycloalkyl group, preferably a 4-7-membered cycloalkyl group, such as cyclobutane, cyclopentane, cyclohexane or cycloheptane.

[0035] In a certain embodiment, each of the 4-10 membered heterocycloalkyl groups is a 4-6 membered heterocycloalkyl group, the heteroatom is selected from one of N, O and S, and the number of heteroatoms is 1, such as cyclopentyl, cyclohexyl, azetidinyl, azocyclopentyl, and azohexyl; the most preferred group is a 6 membered heterocycloalkyl group, the heteroatom is selected from one of N, O and S, and the number of heteroatoms is 1, such as cyclohexyl or azohexyl.

[0036] In a certain embodiment, each amino-protecting group is a conventional amino-protecting group in the art, such as tert-butyloxycarbonyl.

[0037] In a certain embodiment, ring A is a 4-20 membered cycloalkyl or a 4-10 membered heterocycloalkyl, preferably a 4-20 membered cycloalkyl; the heteroatoms in the 4-10 membered heterocycloalkyl are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 4-10 membered heterocycloalkyl are preferably selected from 1 of N, O and S, and the number of heteroatoms is 1.

[0038] In one scenario, R 1 is unsubstituted or one or more R 1-1 A substituted 6-10 membered aryl group (such as phenyl or naphthyl), or an unsubstituted 6-10 membered heteroaryl group, wherein the heteroatoms in the 6-10 membered heteroaryl group are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0039] In one scenario, R 2 is hydrogen or unsubstituted C1-C6 alkyl.

[0040] In one scenario, R 3 and R 4 Each independently is unsubstituted or one or more R 3-1 Substituted 6-10 membered aryl.

[0041] In one scenario, R 6 is hydrogen, unsubstituted C1-C6 alkyl or unsubstituted or one or more R 6-2 Substituted 6-10 membered aryl.

[0042] In one scenario, R 7 It is an amino protecting group.

[0043] In one scenario, R 8 is an unsubstituted C1-C6 alkyl or amino protecting group.

[0044] In one embodiment, in ring A, when the heterocycloalkyl or heterocycloaryl group contains a N atom, an amino protecting group is attached to the N atom.

[0045] In one embodiment, in ring B, when the heterocycloalkyl group contains a N atom, an amino protecting group is attached to the N atom. 1-1 is halogen, unsubstituted or one or more R 1-1-1 Substituted C1-C6 alkyl, unsubstituted or one or more R 1-1-2 Substituted C1-C6 alkoxy, unsubstituted C1-C6 alkylthio.

[0046] In one scenario, R 3-1 It is halogen, unsubstituted C1-C6 alkoxy.

[0047] In one embodiment, Ring A is cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooxolanyl, cyclohexanyl, azetidinyl, azocyclopentanyl or phenylcyclohexanyl.

[0048] In one embodiment, in the compound shown in Formula I, Ring A is A end is connected to the hydroxyl group; preferably

[0049] In one embodiment, in the compound shown in Formula I, Ring A is The a end is connected to the hydroxyl group; preferably

[0050] In a certain embodiment, ring B is oxirane, azocyclopentane or azocyclohexane; preferably azocyclohexane.

[0051] In one embodiment, in the compound shown in formula III, ring B is Best

[0052] In one scenario, R 1-1 It is fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy, trifluoromethoxy, or methylthio.

[0053] In one scenario, R 2 It is hydrogen or ethyl.

[0054] In one scenario, R 1 is phenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4-chlorophenyl, 2-methylphenyl, 3-methylthiophenyl, 4-fluorophenyl, 3-trifluoromethylphenyl, 4-bromo-2-methoxyphenyl, b-naphthyl, 6-benzofuranyl or 5-benzothiophenyl.

[0055] In one scenario, R 3 is phenyl or 4-bromophenyl.

[0056] In one scenario, R 4 It is phenyl or 4-methoxyphenyl.

[0057] In one scenario, R 3-1 is bromine or methoxy.

[0058] In one scenario, R 5 It is 4-methylbenzenesulfonyl.

[0059] In one scenario, R 6 It is hydrogen, methyl, phenyl, 3-trifluoromethylphenyl, 2-methoxy-3-fluorophenyl.

[0060] In one scenario, R 7 It is tert-butyloxycarbonyl.

[0061] In one scenario, R 8 It is methyl or tert-butyloxycarbonyl.

[0062] In one embodiment, m is 0, 1 or 3.

[0063] In one embodiment, n is 0 or 1.

[0064] In a certain embodiment, the compound shown in Formula I is a compound shown in Formula 1, a compound shown in Formula 2, a compound shown in Formula 3, or a compound shown in Formula 4; preferably, a compound shown in Formula 1, a compound shown in Formula 2, or a compound shown in Formula 3;

[0065]

[0066] In a certain embodiment, the compound shown in Formula II is a compound shown in Formula 5 or a compound shown in Formula 6; preferably, the compound shown in Formula 5;

[0067]

[0068] In one embodiment, the compound shown in Formula III is a racemic compound, that is, the compound shown in Formula 7 and

[0069] The ratio of the amount of the compound represented by formula 8 is 1:1

[0070]

[0071] In a certain embodiment, the compound shown in Formula 1 is cis-2-phenylcyclopentan-1-ol, cis-2-(4-methoxyphenyl)cyclopentan-1-ol, cis-2-(4-trifluoromethoxyphenyl)cyclopentan-1-ol, cis-2-(4-chlorophenyl)cyclopentan-1-ol, cis-2-(2-methylphenyl)cyclopentan-1-ol, cis-2-(3-methylthiophenyl)cyclopentan-1-ol, cis-2-(b-naphthyl)cyclopentan-1-ol or cis-2-(5-benzothiophenyl)cyclopentan-1-ol.

[0072] In one embodiment, the compound shown in Formula 2 is trans-2-phenylcyclohexan-1-ol, trans-2-(4-methoxyphenyl)cyclohexan-1-ol, trans-2-(4-fluorophenyl)cyclohexan-1-ol, trans-2-(3-trifluoromethylphenyl)cyclohexan-1-ol, trans-2-(6-benzofuranyl)cyclohexan-1-ol, and trans-2-phenylcycloheptan-1-ol.

[0073] In one embodiment, the compound shown in Formula 3 is trans-2-(4-bromo-2-methoxyphenyl)cyclobutan-1-ol or trans-2-ethyl-2-(4-methoxyphenyl)cyclobutan-1-ol.

[0074] In one embodiment, the compound shown in Formula 5 is trans-N-(2-hydroxy-1,2-diphenylethyl)-4-methylbenzenesulfonamide, trans-N-2-(4-bromophenyl)-2-hydroxy-1-phenylethyl)-4-methylbenzenesulfonamide or trans-N-2-hydroxy-1-(4-methoxyphenyl)-2-phenylethyl)-4-methylbenzenesulfonamide.

[0075] In one embodiment, the compound shown in formula III is 1-tert-butoxycarbonyl-3-hydroxypiperidine, N-tert-butoxycarbonyl-3-phenylpiperidin-3-ol, N-tert-butoxycarbonyl-3-(3-trifluoromethylphenyl)piperidin-3-ol, N-tert-butoxycarbonyl-3-(2-methoxy-3-fluorophenyl)piperidin-3-ol, N-tert-butoxycarbonyl-3-methyl-3-hydroxypiperidine or N-tert-butoxycarbonyl-3,5,5-trimethyl-3-hydroxypiperidine.

[0076] In one embodiment, the compound as shown in formula I-1 is selected from any one of the following compounds:

[0077]

[0078] In a certain embodiment, the compound as shown in formula I-2 is selected from any one of the following compounds:

[0079]

[0080] In a certain embodiment, the compound as shown in formula I-3 is selected from any one of the following compounds:

[0081]

[0082] In one embodiment, the compound as shown in formula II-1 is selected from any one of the following compounds:

[0083]

[0084] In one embodiment, the compound shown in formula III-1 is selected from any one of the following compounds:

[0085]

[0086] In a certain embodiment, the compound shown in formula III-2 is selected from any one of the following compounds:

[0087]

[0088] In the preparation method of the chiral alcohol compound, the chiral bisoxazoline ligand is preferably Best

[0089] In the preparation method of the chiral alcohol compound, when the compound shown in formula I is The ligand is When the product of the method 1 is

[0090] In the preparation method of the chiral alcohol compound, when the compound shown in formula I is The ligand is When the product of the method 1 is

[0091] In the preparation method of the chiral alcohol compound, when the compound shown in formula I is The ligand is When the product of the method 1 is

[0092] In the preparation method of the chiral alcohol compound, when the compound shown in formula I is The ligand is When the product of the method 1 is

[0093] In the preparation method of the chiral alcohol compound, when the compound shown in Formula II is The ligand is a chiral bisoxazoline ligand, and the chiral bisoxazoline ligand is When the product of the second method is

[0094] In the preparation method of the chiral alcohol compound, when the compound shown in Formula II is The ligand is a chiral bisoxazoline ligand, and the chiral bisoxazoline ligand is When the product of the second method is In the method for preparing the chiral alcohol compound, in method 3, when R 6 is hydrogen, and the ligand is When the product of the method three is

[0095] In the preparation method of the chiral alcohol compound, in method 3, when R 6 is unsubstituted or one or more R 6-1 Substituted C1-C6 alkyl or unsubstituted or one or more R 6-2 substituted 6-10 membered aryl, the ligand is When the product of the method three is

[0096] In the method for preparing the chiral alcohol compound, the titanium catalyst is one or more of titanium tetrachloride, titanium tetrabromide and titanium tetraisopropoxide, preferably titanium tetrachloride and / or titanium tetrabromide, more preferably titanium tetrachloride.

[0097] In the preparation method of the chiral alcohol compound, the base is an inorganic base and / or an organic base; the inorganic base is preferably one or more of sodium carbonate, potassium carbonate, lithium carbonate, sodium phosphate and lithium phosphate, more preferably sodium carbonate; the organic base is preferably one or more of diisopropylethylamine, 2,6-lutidine and 2,4,6-trimethylpyridine, more preferably diisopropylethylamine.

[0098] In the preparation method of the chiral alcohol compound, the solvent is one or more of an alkane solvent, a halogenated hydrocarbon solvent and an aromatic hydrocarbon solvent; the alkane solvent is preferably a chain alkane solvent and / or a cycloalkane solvent, the chain alkane is preferably one or more of n-hexane, n-heptane and isooctane, the cycloalkane solvent is preferably cyclohexane; the halogenated hydrocarbon solvent is preferably dichloromethane and / or chloroform; the aromatic hydrocarbon solvent is preferably toluene.

[0099] In the method for preparing the chiral alcohol compound, the molar ratio of the titanium catalyst to the achiral alcohol compound is a conventional molar ratio for this type of reaction in the art, such as 0.001 to 0.5:1, preferably 0.005 to 0.2:1, more preferably 0.005 to 0.1:1, and most preferably 0.01:1, 0.02:1, 0.04:1 or 0.08:1.

[0100] In the preparation method of the chiral alcohol compound, the molar ratio of the ligand to the achiral alcohol compound is a conventional molar ratio for this type of reaction in the art, for example, 0.001 to 1:1, preferably 0.005 to 0.6:1, more preferably 0.005 to 0.3:1, for example, 0.01:1, 0.02:1, 0.04:1, 0.08:1, 0.12:1 or 0.16:1, most preferably 0.01:1, 0.02:1, 0.08:1 or 0.16:1.

[0101] In the method for preparing the chiral alcohol compound, the molar ratio of the base to the achiral alcohol compound is a conventional molar ratio for this type of reaction in the art, such as 0.001 to 1:1, preferably 0.01 to 0.6:1, more preferably 0.04 to 0.3:1, such as 0.04:1, 0.08:1, 0.12:1, 0.16:1 or 0.3:1, most preferably 0.16:1 or 0.3:1.

[0102] In the method for preparing the chiral alcohol compound, the molar ratio of the base to the ligand is a conventional molar ratio for this type of reaction in the art, such as 1 to 5:1, preferably 1 to 3:1, more preferably 1.5:1, 1.875:1, 2:1 or 3:1.

[0103] In the method for preparing the chiral alcohol compound, the molar concentration of the achiral alcohol compound is the conventional molar concentration of this type of reaction in the art, for example, 0.005 to 0.5 mol / L, preferably 0.01 to 0.1 mol / L, more preferably 0.01 to 0.05 mol / L, and most preferably 0.025 mol / L.

[0104] In the method for preparing the chiral alcohol compound, the wavelength of the light is 365-395 nm, for example 365 nm or 395 nm, preferably 395 nm.

[0105] In the method for preparing the chiral alcohol compound, the light source of the illumination is a 365-395 nm LED, such as a 365 nm or 395 nm LED, preferably a 395 nm LED.

[0106] In the preparation method of the chiral alcohol compound, the light intensity of the illumination is 0.02-2.00 W / cm 2 , preferably 0.05-1.80W / cm 2 , for example 0.1W / cm 2 , 0.2W / cm 2 , 0.4W / cm 2 、0.6W / cm 2 or 1.6W / cm 2 , preferably 0.8W / cm 2 .

[0107] In the method for preparing the chiral alcohol compound, the reaction temperature is a conventional reaction temperature for this type of reaction in the art, such as -60 to 30°C, preferably -40 to 20°C, such as 0°C, 20°C, most preferably 0°C or 20°C.

[0108] The method for preparing the chiral alcohol compound can be carried out under aerobic or anaerobic conditions, preferably under anaerobic conditions.

[0109] In the method for preparing the chiral alcohol compound, the reaction time is the conventional reaction time for this type of reaction in the art, such as 2 to 72 hours, preferably 4 to 48 hours, more preferably 4 hours, 6 hours, 12 hours, 18 hours, 24 hours or 48 hours.

[0110] In the preparation method of the chiral alcohol compound, in the method 1, the base is one or more of sodium carbonate, lithium carbonate, sodium phosphate and diisopropylethylamine, preferably one or more of sodium carbonate, lithium carbonate and sodium phosphate.

[0111] In the preparation method of the chiral alcohol compound, in the second method, the base is one or more of sodium carbonate, potassium carbonate, lithium phosphate, diisopropylethylamine and 2,4,6-trimethylpyridine, preferably sodium carbonate and / or potassium carbonate.

[0112] In the method for preparing the chiral alcohol compound, in method three, the base is sodium carbonate.

[0113] Unless otherwise specified, the terms used in the present invention have the following meanings:

[0114] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0115] The term "alkyl" refers to a straight or branched chain alkyl group having a specified number of carbon atoms (e.g., C1 to C6). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.

[0116] The term "alkoxy" refers to a group R X -O-, where R X is an alkyl group as defined above.

[0117] The term "cycloalkyl" refers to a saturated monocyclic ring group consisting only of carbon atoms with a specified number of carbon atoms (e.g., C3-C6). Cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0118] The term "heterocycloalkyl" refers to a cyclic group having a specified number of ring atoms (e.g., 5 to 10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (one or more of N, O, and S), which is a saturated monocyclic ring. Heterocycloalkyl includes, but is not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, piperidinyl, and the like.

[0119] The term "aryl" refers to a group having a specified number of carbon atoms (e.g., C6 to C 10 ) is a cyclic group consisting only of carbon atoms, which is monocyclic or polycyclic, and each ring is aromatic (conforming to Huckel's rule). Aryl includes but is not limited to phenyl, naphthyl, etc.

[0120] The term "heteroaryl" refers to a cyclic group having a specified number of ring atoms (e.g., 5 to 10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (one or more of N, O, and S), which is monocyclic or polycyclic, and each ring is aromatic (in accordance with Huckel's rule). Heteroaryl includes, but is not limited to, furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, indolyl, and the like.

[0121] In the structure fragment It means that the structural fragment is connected to other fragments in the molecule through this site. For example, It refers to cyclohexyl.

[0122] On the basis of being in accordance with the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0123] The reagents and raw materials used in the present invention are commercially available.

[0124] The positive progress of the present invention is that the preparation method of the present invention only needs to add a titanium catalyst and a chiral ligand, and does not need to add any additional oxidant or reducing agent. Only through one-step reaction, a series of achiral alcohol deracemization reactions can be successfully achieved under photocatalysis, and the reaction can control the stereoselectivity of the reaction very well. The method starts from achiral alcohol and can directly and efficiently obtain chiral alcohol with high stereoselectivity through one-step photoreaction. The substrate of the present invention has a wide range of applications and can be applied to a series of cyclic secondary alcohols and tertiary alcohols of different ring systems. In addition to the common five-membered ring and six-membered ring alcohols, the synthetically challenging four-membered ring alcohols, and the 7-15-membered medium-ring and macrocyclic alcohols can also obtain good results. From the structure and function of the alcohol, the present invention is applicable to a series of cyclic piperidine secondary alcohols, tertiary alcohols, etc. with common skeleton structures in drug molecules. In addition, in addition to cyclic alcohols, the present invention can also be extended to chain alcohols. For example, amino alcohols, an important synthetic skeleton, can also achieve good deracemization. BRIEF DESCRIPTION OF THE DRAWINGS

[0125] Figure 1 This is the single crystal diffraction pattern of the product of Example 15.

[0126] Figure 2 This is the single crystal diffraction pattern of the product of Example 23. DETAILED DESCRIPTION

[0127] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0128] The chiral ligands, catalysts and other reagents used in the examples can all be obtained commercially.

[0129] The er value and dr value in the following examples and comparative examples were determined by HPLC analysis using ChiraPak AD-H as a chromatographic column, and the yield was determined by HPLC analysis using 1-Boc-pyrrolidine as an internal standard and by mass calculation of the pure compound obtained by column-level separation and purification.

[0130] The substrate in Example 1-25 is a racemic alcohol compound, and its general synthesis strategy is as shown in Preparation Example 1-4, and the amount of each reagent is a conventional amount. The NMR characterization of the racemic alcohol compound (i.e., the product of Preparation Example 1-4) is the same as that of its corresponding chiral product (i.e., the product of Example 1-25).

[0131] Preparation Example 1: Epoxy ring opening of the Format reagent to obtain the trans-pentacyclic alcohol, followed by configuration inversion to synthesize the cis-pentacyclic alcohol substrate

[0132]

[0133] Operation steps: Step 1: 1,2-epoxycyclopentane is dissolved in tetrahydrofuran solvent, and an equivalent amount of aryl Grignard reagent is slowly added at zero degrees. Trans-2-arylcyclopentanol is obtained by separation and purification.

[0134] Step 2: Dissolve the product of the first step in tetrahydrofuran solvent, add equivalent amounts of p-nitrobenzoic acid, triphenylphosphine and DEAD in sequence, and after the reaction is complete at room temperature, separate and purify the product and hydrolyze it under sodium hydroxide to finally obtain cis-2-arylcyclopentanol.

[0135] The substrates of Examples 1-8 were prepared by the above method.

[0136]

[0137]

[0138] Preparation Example 2 Preparation of trans-hexacyclic alcohol by epoxy ring opening with a grignard reagent

[0139]

[0140] Operation steps: 1,2-epoxycyclohexane is dissolved in tetrahydrofuran solvent, and an equivalent amount of aryl Grignard reagent is slowly added at zero degrees. Trans-2-aryl cyclohexanol is obtained by separation and purification.

[0141] The substrates of Examples 9-13 and 22 were prepared by the above method.

[0142]

[0143]

[0144] Preparation Example 3 Preparation of piperidine tertiary alcohol by addition of Grignard reagent to N-tert-butylcarbonyl-3-one

[0145]

[0146] Operation steps: N-tert-butylcarbonyl-3-piperidone is dissolved in tetrahydrofuran solvent, and an equivalent amount of methyl or aryl Grignard reagent is slowly added at zero degrees. The piperidine tertiary alcohol is separated and purified.

[0147] The substrates of Examples 15-19 were prepared by the above method.

[0148]

[0149]

[0150] Preparation Example 4 Alcohol precursor ketone is prepared into alcohol under sodium borohydride reduction conditions.

[0151]

[0152] Operation steps: The precursor ketone is dissolved in methanol, and an equivalent amount of sodium borohydride is slowly added to separate and purify to obtain the racemic alcohol.

[0153] The substrates of Examples 20-25 were prepared by the above method.

[0154]

[0155] Example 1 Preparation of (1S, 2S)-2-phenylcyclopentan-1-ol

[0156]

[0157] Into an 8 mL glass bottle, cis-2-phenylcyclopentan-1-ol (8.1 mg, 0.05 mmol), chiral ligand (S)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthol phosphate (6.0 mg, 0.008 mmol), sodium carbonate (1.6 mg, 0.015 mmol) and a stirrer were weighed in sequence. After nitrogen was replaced three times, n-heptane (2 mL) and metal catalyst TiCl4 (0.38 mg, 0.002 mmol) were added under anhydrous and oxygen-free conditions. The reaction bottle was then sealed and placed in a temperature-controlled reaction tank (the temperature was set to 20 °C) and illuminated under a 395 nm LEDs lamp (light intensity 0.8 W / cm 2) was subjected to light irradiation for 24 hours. After the light irradiation reaction, the solvent was dried, and the crude product was purified by column chromatography and analyzed by HPLC to obtain (1S, 2S)-2-phenylcyclopentan-1-ol (7.5 mg, yield 93%, 8.8:1 d.r., 99:1 er). The absolute configuration of the product was confirmed by comparing the optical rotation sign with that of the known literature (J.Am.Chem.Soc.2014,136,17591-17600), and the optical rotation sign of (1S, 2S) was positive.

[0158] 1 H NMR (400MHz, CDCl3) δ7.36–7.30(m,4H),7.26–7.22(m,1H),4.30–4.28(m,1H),3.08 –3.02(m,1H),2.16–2.92(m,4H),1.86–1.80(m,1H),1.76–1.68(m,1H),1.27(s,1H); 13 CNMR (100MHz,CDCl3)δ139.9,128.6,128.5,126.6,75.7,52.0,33.7,27.3,22.4; HRMS (EI+):calculated value C 11 H 14 O + (M) + 162.1039, measured value 162.1041; [α] D 25 +56.8 (c 1.0, CHCl3); HPLC analysis: ChiralPak ADH (n-hexane / i-PrOH=97 / 3, flow rate 1.0mL / min, λ=210nm), t R (major)=11.68min,t R (minor) = 14.41min.

[0159] Example 2 Preparation of (1S, 2S)-2-(4-methoxyphenyl)cyclopentan-1-ol

[0160]

[0161] Into an 8 mL glass bottle, cis-2-(4-methoxyphenyl)cyclopentan-1-ol (9.6 mg, 0.05 mmol), chiral ligand (S)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthol phosphate (6.0 mg, 0.008 mmol), sodium carbonate (1.6 mg, 0.015 mmol) and a stirrer were weighed in sequence. After nitrogen was replaced three times, n-heptane (2 mL) and metal catalyst TiCl4 (0.38 mg, 0.002 mmol) were added under anhydrous and oxygen-free conditions. The reaction bottle was then sealed and placed in a temperature-controlled reaction tank (the temperature was set to 20 °C) and illuminated under a 395 nm LEDs lamp (light intensity 0.8 W / cm 2 ) was subjected to light irradiation for 24 hours. After the light irradiation reaction, the solvent was dried, and the crude product was purified by column chromatography and analyzed by HPLC to obtain (1S, 2S)-2-(4-methoxyphenyl)cyclopentan-1-ol (8.9 mg, yield 93%, 14:1 d.r., 98:2 er). The absolute configuration of the product was confirmed by comparing the optical rotation symbol with that of Example 1.

[0162] 1 H NMR (400MHz, CDCl3) δ7.25–7.21(m,2H),6.91–6.87(m,2H),4.26–4.23(m,1H),3.80(s,3H) ,3.04–2.98(m,1H),2.11–1.90(m,4H),1.87–1.79(m,1H),1.75–1.65(m,1H),1.22(s,1H); 13 C NMR (100 MHz, CDCl3) δ 158.4, 131.7, 129.5, 114.0, 75.7, 55.2, 51.1, 33.7, 27.6, 22.4; HRMS (EI+): calculated value C 12 H 16 O2 + (M) + 192.1145, measured value 192.1141; [α] D 25.0 +28.1 (c1.0, CHCl3); HPLC analysis: ChiralPak ADH (n-hexane / i-PrOH=95 / 5, flow rate 1.0mL / min, λ=210nm), t R (major)=12.73min,t R (minor) = 13.46min.

[0163] Example 3 Preparation of (1S, 2S)-2-(4-trifluoromethoxyphenyl)cyclopentan-1-ol

[0164]

[0165] Into an 8 mL glass bottle, cis-2-(4-trifluoromethoxyphenyl)cyclopentan-1-ol (12.3 mg, 0.05 mmol), chiral ligand (S)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthol phosphate (6.0 mg, 0.008 mmol), sodium carbonate (1.6 mg, 0.015 mmol) and a stirrer were weighed in sequence. After nitrogen was replaced three times, n-heptane (2 mL) and metal catalyst TiCl4 (0.38 mg, 0.002 mmol) were added under anhydrous and oxygen-free conditions. The reaction bottle was then sealed and placed in a temperature-controlled reaction tank (the temperature was set to 20 °C) and illuminated under a 395 nm LEDs lamp (light intensity 0.8 W / cm 2 ) was subjected to light irradiation for 24 hours. After the light irradiation reaction, the solvent was dried, and the crude product was purified by column chromatography and analyzed by HPLC to obtain (1S, 2S)-2-(4-trifluoromethoxyphenyl)cyclopentan-1-ol (11.7 mg, yield 95%, 4:1 d.r., 95:5 er). The absolute configuration of the product was confirmed by comparing the optical rotation sign with that of Example 1.

[0166] 1 H NMR(400MHz, CDCl3)δ7.33(d,J=8.4Hz,2H),7.19(d,J=8.4Hz,2H),4.31–4.29(m,1H),3 .06–3.01(m,1H),2.13–1.94(m,4H),1.87–1.80(m,1H),1.77–1.67(m,1H),1.12(s,1H); 13 C NMR (100MHz, CDCl3) δ147.9, 138.8, 129.9, 120.9, 120.4 (q, J = 255Hz), 75.6, 51.3, 34.0, 27.8, 22.3; 19 F NMR (375MHz,CDCl3)δ–57.8.HRMS (EI+): Calculated value C 12 H 13 F3O2 + (M) + 246.0862, measured value 246.0869; [α] D 25.0 +36.4 (c 1.0, CHCl3); HPLC analysis: ChiralPak ADH (n-hexane / i-PrOH=98 / 2, flow rate 1.0mL / min, λ=210nm), t R (major)=7.84min,tR (minor) = 8.52min.

[0167] Example 4 Preparation of (1S, 2S)-2-(4-chlorophenyl)cyclopentan-1-ol

[0168]

[0169] Into an 8 mL glass bottle, cis-2-(4-chlorophenyl)cyclopentan-1-ol (9.8 mg, 0.05 mmol), chiral ligand (S)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthol phosphate (6.0 mg, 0.008 mmol), sodium carbonate (1.6 mg, 0.015 mmol) and a stirrer were weighed in sequence. After nitrogen was replaced three times, n-heptane (2 mL) and metal catalyst TiCl4 (0.38 mg, 0.002 mmol) were added under anhydrous and oxygen-free conditions. The reaction bottle was then sealed and placed in a temperature-controlled reaction tank (set to 20 °C) and illuminated under a 395 nm LEDs lamp (light intensity 0.8 W / cm 2 ) was subjected to light irradiation for 24 hours. After the light irradiation reaction, the solvent was dried, and the crude product was purified by column chromatography and analyzed by HPLC to separate the chiral alcohol (1S, 2S)-2-(4-chlorophenyl)cyclopentan-1-ol (8.8 mg, yield 90%, 6:1 d.r., 97:3 er). The absolute configuration of the product was confirmed by comparing the optical rotation sign with that of Example 1.

[0170] 1 H NMR (400MHz, CDCl3) δ7.32–7.29(m,2H),7.25–7.22(m,2H),4.28–4.26(m,1H),3.03 –2.97(m,1H),2.10–1.92(m,4H),1.85–1.78(m,1H),1.75–1.68(m,1H),1.13(s,1H); 13 CNMR (100MHz,CDCl3)δ138.5,132.3,129.9,128.5,75.6,51.3,34.0,27.6,22.3; HRMS (EI+):calculated value C 11 H 13 C1O + (M) + 196.0649, measured value 196.0646; [α] D 25.0 +56.2 (c 1.0, CHCl3); HPLC analysis: ChiralPak ADH (n-hexane / i-PrOH=98 / 2, flow rate 1.0mL / min, λ=210nm), tR (major)=11.43min,t R (minor) = 12.35min.

[0171] Example 5 Preparation of (1S, 2S)-2-(2-methylphenyl)cyclopentan-1-ol:

[0172]

[0173] Into an 8 mL glass bottle, cis-2-(2-methylphenyl)cyclopentan-1-ol (8.8 mg, 0.05 mmol), chiral ligand (S)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthol phosphate (6.0 mg, 0.008 mmol), sodium carbonate (1.6 mg, 0.015 mmol) and a stirrer were weighed in sequence. After nitrogen was replaced three times, n-heptane (2 mL) and metal catalyst TiCl4 (0.38 mg, 0.002 mmol) were added under anhydrous and oxygen-free conditions. The reaction bottle was then sealed and placed in a temperature-controlled reaction tank (set to 20 °C) and illuminated under a 395 nm LEDs lamp (light intensity 0.8 W / cm 2 ) was subjected to light irradiation for 24 hours. After the light irradiation reaction, the solvent was dried, and the crude product was purified by column chromatography and analyzed by HPLC to obtain (1S, 2S)-2-(2-methylphenyl)cyclopentan-1-ol (8.4 mg, yield 95%, 3.2:1 d.r., 94:6 er). The absolute configuration of the product was confirmed by comparing the optical rotation sign with that of Example 1.

[0174] 1 H NMR(400MHz, CDCl3)δ7.34(d,1H,J=7.6Hz),7.23–7.14(m,3H),4.31–4.29(m,1H),3.25–3.19(m,1H), 2.37(s,3H),2.25–2.15(m,1H),2.11–1.95(m,2H),1.89–1.81(m,2H),1.72–1.64(m,1H),1.00(s,1H); 13 C NMR (100 MHz, CDCl3) δ 137.3, 136.9, 130.5, 127.7, 126.6, 125.9, 73.1, 48.3, 34.0, 27.8, 22.4, 19.9; HRMS (EI+): calculated value C 12 H 16 O + (M) + 176.1196, measured value 176.1191; [α] D 25.0+103.7 (c 0.5, CHCl3); HPLC analysis: ChiralPak ADH (n-hexane / i-PrOH=97 / 3, flow rate 1.0mL / min, λ=210nm), t R (major) = 9.53min,t R (minor) = 12.27min.

[0175] Example 6 Preparation of (1S, 2S)-2-(3-methylthiophenyl)cyclopentan-1-ol:

[0176]

[0177] Into an 8 mL glass bottle, cis-2-(3-methylthiophenyl)cyclopentan-1-ol (10.4 mg, 0.05 mmol), chiral ligand (S)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthol phosphate (6.0 mg, 0.008 mmol), sodium carbonate (1.6 mg, 0.015 mmol) and a stirrer were weighed in sequence. After nitrogen was replaced three times, n-heptane (2 mL) and metal catalyst TiCl4 (0.38 mg, 0.002 mmol) were added under anhydrous and oxygen-free conditions. The reaction bottle was then sealed and placed in a temperature-controlled reaction tank (set to 20 °C) and illuminated under a 395 nm LEDs lamp (light intensity 0.8 W / cm 2 ) was subjected to light irradiation for 24 hours. After the light irradiation reaction, the solvent was dried, and the crude product was purified by column chromatography and analyzed by HPLC to obtain (1S, 2S)-2-(3-methylthiophenyl)cyclopentan-1-ol (9.4 mg, yield 90%, 9:1 d.r., 98:2 er). The absolute configuration of the product was confirmed by comparing the optical rotation sign with that of Example 1.

[0178] 1 H NMR (400MHz, CDCl3) δ7.28–7.24(m,1H),7.20(s,1H),7.15–7.12(m,1H),7.08(d,J=7.6Hz,1H),4.30–4.28(m ,1H),3.04–2.98(m,1H),2.49(s,3H),2.14–1.91(m,4H),1.87–1.79(m,1H),1.76–1.67(m,1H),1.21(s,1H); 13 C NMR (100 MHz, CDCl3) δ 140.7, 138.7, 128.9, 126.8, 125.3, 124.7, 75.7, 51.9, 33.8, 27.3, 22.3, 15.7; HRMS (EI+): calculated value C 12 H16 OS + (M) + 208.0916, measured value 208.0912; [α] D 25.0 +71.6 (c 1.0, CHCl3); HPLC analysis: ChiralPak ADH (n-hexane / i-PrOH=95 / 5, flow rate 1.0mL / min, λ=210nm), t R (major)=13.46min,t R (minor) = 15.74min.

[0179] Example 7 Preparation of (1S, 2S)-2-(β-naphthyl)cyclopentan-1-ol:

[0180]

[0181] Into an 8 mL glass bottle, cis-2-(β-naphthyl)cyclopentan-1-ol (10.6 mg, 0.05 mmol), chiral ligand (S)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthol phosphate (6.0 mg, 0.008 mmol), sodium carbonate (1.6 mg, 0.015 mmol) and a stirrer were weighed in sequence. After nitrogen was replaced three times, n-heptane (2 mL) and metal catalyst TiCl4 (0.38 mg, 0.002 mmol) were added under anhydrous and oxygen-free conditions. The reaction bottle was then sealed and placed in a temperature-controlled reaction tank (set to 20 °C) and illuminated under a 395 nm LEDs lamp (light intensity 0.8 W / cm 2 ) was subjected to light irradiation for 24 hours. After the light irradiation reaction, the solvent was dried, and the crude product was purified by column chromatography and analyzed by HPLC to obtain (1S, 2S)-2-(β-naphthyl)cyclopentan-1-ol (9.9 mg, yield 94%, 6.5:1 d.r., 93:7 er). The absolute configuration of the product was confirmed by comparing the optical rotation sign with that of Example 1.

[0182] 1 H NMR (400MHz, CDCl3) δ7.84–7.82(m,3H),7.76(s,1H),7.51–7.44(m,3H),4.41–4.39(m,1H),3.26–3. 20(m,1H),2.31–2.21(m,1H),2.12–2.02(m,3H),1.94–1.86(m,1H),1.83–1.73(m,1H),1.17(s,1H); 13C NMR (100 MHz, CDCl3) δ 137.3, 133.5, 132.4, 128.1, 127.7, 127.6, 127.3, 126.8, 126.1, 125.6, 75.7, 52.2, 33.8, 27.4, 22.5; HRMS (EI+): calculated value C 15 H 16 O + (M) + 212.1196, measured value 212.1193; [α] D 25.0 +54.8 (c 1.0, CHCl3); HPLC analysis: ChiralPakADH (n-hexane / i-PrOH=95 / 5, flow rate 1.0mL / min, λ=210nm), t R (major)=15.90min,t R (minor) = 14.34min.

[0183] Example 8 Preparation of (1S, 2S)-2-(5-benzothiophenyl)cyclopentan-1-ol:

[0184]

[0185] Into an 8 mL glass bottle, cis-2-(5-benzothiophenyl)cyclopentan-1-ol (10.9 mg, 0.05 mmol), chiral ligand (S)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthol phosphate (6.0 mg, 0.008 mmol), sodium carbonate (1.6 mg, 0.015 mmol) and a stirrer were weighed in sequence. After nitrogen was replaced three times, n-heptane (2 mL) and metal catalyst TiCl4 (0.38 mg, 0.002 mmol) were added under anhydrous and oxygen-free conditions. The reaction bottle was then sealed and placed in a temperature-controlled reaction tank (set to 20 °C) and illuminated under a 395 nm LEDs lamp (light intensity 0.8 W / cm 2 ) was subjected to light irradiation for 24 hours. After the light irradiation reaction, the solvent was dried, and the crude product was purified by column chromatography and analyzed by HPLC to obtain (1S, 2S)-2-(5-benzothiophenyl)cyclopentan-1-ol (10.1 mg, yield 93%, 9:1 d.r., 95:5 er). The absolute configuration of the product was confirmed by comparing the optical rotation sign with that of Example 1.

[0186] 1H NMR (400MHz, CDCl3) δ7.85(d,J=8.4Hz,1H),7.77(s,1H),7.45(d,J=5.2Hz,1H),7.33–7.29(m,2H),4.36–4.33(m, 1H),3.22–3.16(m,1H),2.24–2.14(m,1H),2.10–1.99(m,3H),1.92–1.84(m,1H),1.82–1.70(m,1H),1.22(s,1H); 13 C NMR (100 MHz, CDCl3) δ 140.0, 138.1, 135.9, 126.8, 125.3, 123.7, 123.2, 122.5, 75.8, 51.9, 33.8, 27.6, 22.5; HRMS (EI+): calculated value C 13 H 14 OS + (M) + 218.0760, measured value 218.0761; [α] D 25.0 +55.1 (c 1.0, CHCl3); HPLC analysis: ChiralPak IB (n-hexane / i-PrOH=95 / 5, flow rate 1.0mL / min, λ=210nm), t R (major)=13.16min,t R (minor) = 14.07min.

[0187] Example 9 Preparation of (1R, 2S)-2-phenylcyclohexan-1-ol:

[0188]

[0189] Into an 8 mL glass bottle, trans-2-phenylcyclohexan-1-ol (8.8 mg, 0.05 mmol), chiral ligand (R)-3,3'-bis(4-perfluorobiphenyl)-1,1'-binaphthol phosphate (3.9 mg, 0.004 mmol), sodium carbonate (0.8 mg, 0.008 mmol) and a stirrer were weighed in sequence. After nitrogen was replaced three times, isooctane (2 mL) and metal catalyst TiCl4 (0.19 mg, 0.001 mmol) were added under anhydrous and oxygen-free conditions. The reaction bottle was then sealed and placed in a temperature-controlled reaction tank (set to 20 °C) and illuminated under a 395 nm LEDs lamp (light intensity 0.W / cm 2) was subjected to light-induced reaction for 4 hours. After the light-induced reaction, the solvent was dried, and the crude product was purified by column chromatography and analyzed by HPLC to obtain (1R, 2S)-2-(phenyl)cyclohexan-1-ol (8.4 mg, yield 96%, 13:1 d.r., 96:4 er). The absolute configuration of the product was confirmed by comparing the optical rotation sign with that of the known literature (J.Am.Chem.Soc.2014,136,17591-17600), and the optical rotation sign of (1R,2S) was negative.

[0190] 1 H NMR (400MHz, CDCl3) δ7.34–7.30(m,2H),7.25–7.20(m,3H),3.67–3.61(m,1H),2.45–2.38(m, 1H),2.11–2.09(m,1H),1.86–1.84(m,2H),1.77–1.74(m,1H),1.60(s,1H),1.56–1.30(m,4H); 13 C NMR (100 MHz, CDCl3) δ 143.2, 128.7, 127.8, 126.7, 74.3, 53.1, 34.3, 33.2, 26.0, 25.0; HRMS (EI+): calculated value C 12 H 16 O + (M) + 176.1196, measured value 176.1192; [α] D 25.0 –50.7 (c 1.0, MeOH); HPLC analysis: ChiralPak ADH (n-hexane / i-PrOH=95 / 5, flow rate 1.0mL / min, λ=210nm), t R (major)=11.38min,t R (minor) = 10.19min.

[0191] Example 10 Preparation of (1R, 2S)-2-(4-methoxyphenyl)cyclohexan-1-ol:

[0192]

[0193] Into an 8 mL glass bottle, trans-2-(4-methoxyphenyl)cyclohexan-1-ol (10.3 mg, 0.05 mmol), chiral ligand (R)-3,3'-bis(4-perfluorobiphenyl)-1,1'-binaphthol phosphate (3.9 mg, 0.004 mmol), sodium carbonate (0.8 mg, 0.008 mmol) and a stirrer were weighed in sequence. After nitrogen was replaced three times, isooctane (2 mL) and metal catalyst TiCl4 (0.19 mg, 0.001 mmol) were added under anhydrous and oxygen-free conditions. The reaction bottle was then sealed and placed in a temperature-controlled reaction tank (set to 20 °C) and illuminated under a 395 nm LEDs lamp (light intensity 0.8 W / cm 2 ) was subjected to light irradiation for 4 hours. After the light irradiation reaction, the solvent was dried, and the crude product was purified by column chromatography and analyzed by HPLC to obtain (1R, 2S)-2-(4-methoxyphenyl)cyclohexan-1-ol (9.7 mg, yield 94%, 4:1 d.r., 92:8 er). The absolute configuration of the product was confirmed by comparing the optical rotation symbol with that of Example 9.

[0194] 1 H NMR (400MHz, CDCl3) δ7.17(d,J=8.8Hz,2H),6.88(d,J=8.8Hz,2H),3.80(s,3H),3.62–3.56(m,1H),2.41 –2.34(m,1H),2.13–2.08(m,1H),1.86–1.81(m,2H),1.78–1.73(m,1H),1.63(s,1H),1.54–1.26(m,4H); 13 C NMR (100 MHz, CDCl3) δ 158.4, 135.1, 128.7, 114.1, 74.5, 55.2, 52.3, 34.4, 33.4, 26.1, 25.0; HRMS (EI+): calculated value C 13 H 18 O2 + (M) + 206.1301, measured value 206.1297; [α] D 25.0 –45.9 (c 1.0, MeOH); HPLC analysis: ChiralPak ADH (n-hexane / i-PrOH=95 / 5, flow rate 1.0mL / min, λ=210nm), t R (major)=18.98min,t R (minor) = 15.93min.

[0195] Example 11 Preparation of (1R, 2S)-2-(4-fluorophenyl)cyclohexan-1-ol:

[0196]

[0197] Into an 8 mL glass bottle, trans-2-(4-fluorophenyl)cyclohexan-1-ol (9.7 mg, 0.05 mmol), chiral ligand (R)-3,3'-bis(4-perfluorobiphenyl)-1,1'-binaphthol phosphate (3.9 mg, 0.004 mmol), sodium carbonate (0.8 mg, 0.008 mmol) and a stirrer were weighed in sequence. After nitrogen was replaced three times, isooctane (2 mL) and metal catalyst TiCl4 (0.19 mg, 0.001 mmol) were added under anhydrous and oxygen-free conditions. The reaction bottle was then sealed and placed in a temperature-controlled reaction tank (set to 20 °C) and illuminated under a 395 nm LEDs lamp (light intensity 0.8 W / cm 2 ) was photo-exposed for 4 hours. After the photo-exposed reaction, the solvent was dried, and the crude product was purified by column chromatography and analyzed by HPLC to obtain (1R, 2S)-2-(4-fluorophenyl)cyclohexan-1-ol (9.1 mg, yield 94%, 13:1 d.r., 94:6 er). The absolute configuration of the product was confirmed by comparing the optical rotation sign with that of the known literature (J.Am.Chem.Soc.2014,136,17591-17600), and the optical rotation sign of (1R, 2S) was negative.

[0198] 1 H NMR (400MHz, CDCl3) δ7.23–7.19(m,2H),7.04–6.99(m,2H),3.63–3.57(m,1H),2.45–2. 38(m,1H),2.12–2.09(m,1H),1.87–1.81(m,2H),1.78–1.74(m,1H),1.56–1.26(m,5H); 13 C NMR (100MHz, CDCl3) δ161.6 (d, J = 243Hz), 138.9 (d, J = 4Hz), 129.1 (d, J = 8Hz), 115.4 (d, J = 21Hz), 74.4, 52.4, 34.6, 33.5, 26.0, 25.0; 19 F NMR (375 MHz, CDCl3) δ–116.4; HRMS (EI+): calculated value C 12 H 15 FO + (M) + 194.1101, measured value 194.1101; [α] D 25.0–28.7 (c 0.5, MeOH); HPLC analysis: ChiralPak ADH (n-hexane / i-PrOH=95 / 5, flow rate 1.0mL / min, λ=210nm), t R (major)=13.74min,t R (minor) = 11.13min.

[0199] Example 12 Preparation of (1R, 2S)-2-(3-trifluoromethylphenyl)cyclohexan-1-ol:

[0200]

[0201] Into an 8 mL glass bottle, trans-2-(3-trifluoromethylphenyl)cyclohexan-1-ol (12.2 mg, 0.05 mmol), chiral ligand (R)-3,3'-bis(4-perfluorobiphenyl)-1,1'-binaphthol phosphate (3.9 mg, 0.004 mmol), sodium carbonate (0.8 mg, 0.008 mmol) and a stirrer were weighed in sequence. After nitrogen was replaced three times, isooctane (2 mL) and metal catalyst TiCl4 (0.19 mg, 0.001 mmol) were added under anhydrous and oxygen-free conditions. The reaction bottle was then sealed and placed in a temperature-controlled reaction tank (set to 20 °C) and illuminated under a 395 nm LEDs lamp (light intensity 0.8 W / cm 2 ) was subjected to light irradiation for 4 hours. After the light irradiation reaction, the solvent was dried, and the crude product was purified by column chromatography and analyzed by HPLC to obtain (1R, 2S)-2-(3-trifluoromethylphenyl)cyclohexan-1-ol (11.6 mg, yield 95%, 20:1 d.r., 91:9 er). The absolute configuration of the product was confirmed by comparing the optical rotation symbol with that of Example 9.

[0202] 1 H NMR (400MHz, CDCl3) δ7.51–7.48(m,2H),7.45–7.43(m,2H),3.71–3.65(m,1H),2.54–2. 48(m,1H),2.14–2.10(m,1H),1.89–1.86(m,2H),1.81–1.76(m,1H),1.56–1.26(m,5H); 13 C NMR (100MHz, CDCl3) δ144.6, 131.4, 130.9 (q, J = 32Hz), 129.0, 124.5 (q, J = 4H z), 124.1 (q, J = 271Hz), 123.5 (q, J = 4Hz), 74.1, 52.9, 34.8, 33.3, 25.8, 24.9; 19F NMR (375 MHz, CDCl3) δ–62.5; HRMS (EI+): calculated value C 13 H 15 F3O + (M) + 244.1070, measured value 244.1067; [α] D 25.0 –33.2 (c 1.0, MeOH); HPLC analysis: ChiralPak ADH (n-hexane / i-PrOH=97 / 3, flow rate 1.0mL / min, λ=210nm), t R (major)=16.52min,t R (minor) = 13.74min.

[0203] Example 13 Preparation of (1R, 2S)-2-(6-benzofuranyl)cyclohexan-1-ol:

[0204]

[0205] Into an 8 mL glass bottle, trans-2-(6-benzofuranyl)cyclohexan-1-ol (10.8 mg, 0.05 mmol), chiral ligand (R)-3,3'-bis(4-perfluorobiphenyl)-1,1'-binaphthol phosphate (3.9 mg, 0.004 mmol), sodium carbonate (0.8 mg, 0.008 mmol) and a stirrer were weighed in sequence. After nitrogen was replaced three times, isooctane (2 mL) and metal catalyst TiCl4 (0.19 mg, 0.001 mmol) were added under anhydrous and oxygen-free conditions. The reaction bottle was then sealed and placed in a temperature-controlled reaction tank (set to 20 °C) and illuminated under a 395 nm LEDs lamp (light intensity 0.8 W / cm 2 ) was subjected to light irradiation for 4 hours. After the light irradiation reaction, the solvent was dried, and the crude product was purified by column chromatography and analyzed by HPLC to obtain chiral alcohol (1R, 2S)-2-(6-benzofuranyl)cyclohexan-1-ol (9.8 mg, yield 91%, 9:1 d.r., 96:4 er). The absolute configuration of the product was confirmed by comparing the optical rotation symbol with that of Example 9.

[0206] 1H NMR (400MHz, CDCl3) δ7.63(d,J=2.4Hz,1H),7.48(dd,J=7.2,1.6Hz,1H),7.23–7.16(m,2H),6.77(d,J=2.4Hz,1 H),4.03–3.97(m,1H),3.02–2.96(m,1H),2.18-2.15(m,1H),1.95–1.75(m,4H),1.61(s,1H),1.55–1.35(m,3H); 13 C NMR (100 MHz, CDCl3) δ 153.6, 144.6, 127.6, 127.2, 123.1, 123.0, 119.4, 106.7, 73.2, 48.3, 34.8, 31.9, 26.0, 25.0; HRMS (EI+): calculated value C 14 H 16 O2 + (M) + 216.1145, measured value 216.1147; [α] D 25.0 –47.7 (c 1.0, MeOH); HPLC analysis: ChiralPak ADH (n-hexane / i-PrOH=95 / 5, flow rate 1.0mL / min, λ=210nm), t R (major)=16.48min,t R (minor) = 17.39min.

[0207] Example 14 Preparation of (S)-1-tert-butyloxycarbonyl-3-hydroxypiperidine:

[0208]

[0209] 1-tert-Butyloxycarbonyl-3-hydroxypiperidine (10.1 mg, 0.05 mmol), chiral ligand (R)-3,3'-bis(4-perfluorobiphenyl)-1,1'-binaphthol phosphate (7.8 mg, 0.008 mmol), sodium carbonate (1.6 mg, 0.015 mmol) and a stirrer were weighed in an 8 mL glass bottle. After nitrogen was replaced three times, chloroform (2 mL) and metal catalyst TiCl4 (0.38 mg, 0.002 mmol) were added under anhydrous and oxygen-free conditions. The reaction bottle was then sealed and placed in a temperature-controlled reaction tank (set to -40 °C) and illuminated under a 395 nm LEDs lamp (light intensity 0.8 W / cm 2) and light-reacted for 48 hours. After the light-reaction was completed, the solvent was dried, and the crude product was purified by column chromatography and analyzed by HPLC to separate (S)-1-tert-butyloxycarbonyl-3-hydroxypiperidine (9.5 mg, yield 94%, 91:9er). The absolute configuration of the product was confirmed by comparing the optical rotation symbol with that of the commercial reagent (S)-1-tert-butyloxycarbonyl-3-hydroxypiperidine. The product is an important chiral structural unit in the marketed drug molecules Zamifenacin, Piperidolate, and Benidipine.

[0210] 1 H NMR (400MHz, CDCl3) δ3.78–3.50(m,3H),3.11–2.96(m,2H),2.53(br,1H),1.91–1.84(m,1H),1.77–1.69(m,1H),1.53–1.39(m,11H); 13 C NMR (100 MHz, CDCl3) δ 155.2, 79.7, 66.1, 50.6, 44.1, 32.5, 28.4, 22.4; HRMS (ESI+): calculated value C 10 H 19 NO3Na + (M+Na) + 224.12571, measured value 224.12656; [α] D 25.0 +16.4 (c 1.0, EtOH); HPLC analysis: ChiralPak IB (n-hexane / i-PrOH=97 / 3, flow rate 1.0mL / min, λ=210nm), t R (major)=11.13min,t R (minor) = 12.55min.

[0211] Example 15 Preparation of (S)-N-tert-butyloxycarbonyl-3-phenylpiperidin-3-ol:

[0212]

[0213] Into an 8 mL glass bottle, N-tert-butyloxycarbonyl-3-phenylpiperidin-3-ol (13.9 mg, 0.05 mmol), chiral ligand (S)-3,3'-bis(b-perfluoronaphthyl)-1,1'-binaphthol phosphate (3.4 mg, 0.004 mmol), sodium carbonate (0.8 mg, 0.008 mmol) and a stirrer were weighed in sequence. After nitrogen was replaced three times, isooctane (2 mL) and metal catalyst TiCl4 (0.19 mg, 0.001 mmol) were added under anhydrous and oxygen-free conditions. The reaction bottle was then sealed and placed in a temperature-controlled reaction tank (the temperature was set to 20 °C) and illuminated under a 395 nm LEDs lamp (light intensity 0.8 W / cm 2 ) was subjected to light irradiation for 12 hours. After the light irradiation reaction, the solvent was dried, and the crude product was purified by column chromatography and analyzed by HPLC to obtain (S)-N-tert-butyloxycarbonyl-3-phenylpiperidin-3-ol (13.1 mg, yield 94%, 98:2er). The absolute configuration of the product was confirmed by single crystal X-ray diffraction. The single crystal diffraction pattern is shown in Figure 1 . XRD characterization data CCDC:2265923.

[0214] Crystallographic data and structural modification of the product

[0215]

[0216]

[0217] 1 H NMR (400 MHz, CDCl3) δ7.51(d,J=7.2 Hz,2H),7.39–7.35(m,2H),7.30–7.26(m,1H),4.09(d,J=13.2 Hz,1H),4.00–3.97(m,1H),3.19(d,J=13.2 Hz,1H),2.90–2.83(m,1H),2.44(br,1H),2.00–1.89(m,3H),1.63–1.54(m,1H),1.47(s,9H); 13 C NMR (100 MHz, CDCl3) δ 143.3, 128.3, 127.3, 124.8, 80.0, 71.8, 54.8, 44.1, 36.8, 28.4, 21.3; HRMS (ESI+): calculated value C 16 H 23 NO3Na + (M+Na) + 300.15701, measured value 300.15753; [α] D 25.0+61.2 (c 1.0, CHCl3); HPLC analysis: ChiralPak ADH (n-hexane / i-PrOH=97 / 3, flow rate 1.0mL / min, λ=210nm), t R (major)=14.40min,t R (minor) = 18.04min.

[0218] Example 16 Preparation of (S)-N-tert-butyloxycarbonyl-3-(3-trifluoromethylphenyl)piperidin-3-ol:

[0219]

[0220] Into an 8 mL glass bottle, N-tert-butyloxycarbonyl-3-(3-trifluoromethylphenyl)piperidin-3-ol (17.3 mg, 0.05 mmol), chiral ligand (S)-3,3'-bis(b-perfluoronaphthyl)-1,1'-binaphthol phosphate (3.4 mg, 0.004 mmol), sodium carbonate (0.8 mg, 0.008 mmol) and a stirrer were weighed in sequence. After nitrogen was replaced three times, isooctane (2 mL) and metal catalyst TiCl4 (0.19 mg, 0.001 mmol) were added under anhydrous and oxygen-free conditions. The reaction bottle was then sealed and placed in a temperature-controlled reaction tank (the temperature was set to 20 °C) and illuminated under a 395 nm LEDs lamp (light intensity 0.8 W / cm 2 ) was subjected to light irradiation for 12 hours. After the light irradiation reaction, the solvent was dried, and the crude product was purified by column chromatography and analyzed by HPLC to obtain (S)-N-tert-butyloxycarbonyl-3-(3-trifluoromethylphenyl)piperidin-3-ol (15.6 mg, yield 90%, 96:4er). The absolute configuration of the product was confirmed by comparing the optical rotation symbol with that of Example 15.

[0221] 1 H NMR (400MHz, CDCl3) δ7.80(s,1H),7.70(d,J=8.0Hz,1H),7.55(d,J=8.0Hz,1H),7.50–7.46(m,1H),4.09(d,J=13.6Hz,1H),4. 01–3.91(m,1H),3.19(d,J=13.6Hz,1H),2.93–2.86(m,1H),2.72(br,1H),2.00–1.88(m,3H),1.63–1.59(m,1H),1.47(s,9H); 13CNMR(100MHz, CDCl3)δ146.5,130.6(q,J=32Hz),128.8,128.4,124.2(q,J=271H z), 124.1 (q, J = 3Hz), 121.8 (q, J = 4Hz), 80.3, 71.8, 54.5, 44.3, 36.8, 28.4, 21.2; 19 F NMR (375 MHz, CDCl3) δ–62.5; HRMS (ESI+): calculated value C 17 H 22 NO3F3Na + (M+Na) + 368.14440, measured value 368.14484; [α] D 25.0 +40.9 (c 1.0, CHCl3); HPLC analysis: ChiralPak IA (n-hexane / i-PrOH=97 / 3, flow rate 1.0mL / min, λ=210nm), t R (major) = 9.22min, t R (minor) = 8.45min.

[0222] Example 17 Preparation of (S)-N-tert-butyloxycarbonyl-3-(2-methoxy-3-fluorophenyl)piperidin-3-ol:

[0223]

[0224] Into an 8 mL glass bottle, N-tert-butyloxycarbonyl-3-(2-methoxy-3-fluorophenyl)piperidin-3-ol (16.3 mg, 0.05 mmol), chiral ligand (S)-3,3'-bis(b-perfluoronaphthyl)-1,1'-binaphthol phosphate (3.4 mg, 0.004 mmol), sodium carbonate (0.8 mg, 0.008 mmol) and a stirrer were weighed in sequence. After nitrogen was replaced three times, isooctane (2 mL) and metal catalyst TiCl4 (0.19 mg, 0.001 mmol) were added under anhydrous and oxygen-free conditions. The reaction bottle was then sealed and placed in a temperature-controlled reaction tank (set to 20 °C) and illuminated under a 395 nm LEDs lamp (light intensity 0.8 W / cm 2 ) was subjected to light irradiation for 12 hours. After the light irradiation reaction, the solvent was dried, and the crude product was purified by column chromatography and analyzed by HPLC to obtain (S)-N-tert-butyloxycarbonyl-3-(2-methoxy-3-fluorophenyl)piperidin-3-ol (15.5 mg, yield 95%, 94:6er). The absolute configuration of the product was confirmed by comparing the optical rotation symbol with that of Example 15.

[0225] 1H NMR (400MHz, CDCl3) δ7.22 (d, J=7.6Hz, 1H), 7.07–6.96 (m, 2H), 4.15–3.99 (m, 5H), 3.47 (s, 1H) ,3.27(d,J=13.6Hz,1H),2.91–2.85(m,1H),2.17–1.89(m,3H),1.59–1.53(m,1H),1.48(s,9H); 13 C NMR (100MHz, CDCl3) δ155.6 (d, J = 246Hz), 145.5 (d, J = 11Hz), 138.8, 123.2 (d, J = 8Hz), 121. 7(d,J=3Hz),116.4(d,J=20Hz),79.7,72.5,61.4(d,J=9Hz),52.6,43.7,34.7,28.5,21.2; 19 F NMR (375 MHz, CDCl3) δ–129.0; HRMS (ESI+): calculated value C 17 H 24 NO4F + (M+Na) + 348.15816, measured value 348.15907; [α] D 25.0 +49.8 (c 1.0, CHCl3); HPLC analysis: ChiralPak ADH (n-hexane / i-PrOH=97 / 3, flow rate 1.0mL / min, λ=210nm), t R (major)=8.88min,t R (minor) = 10.44min.

[0226] Example 18 Preparation of (R)-N-tert-butyloxycarbonyl-3-methyl-3-hydroxypiperidine:

[0227]

[0228] Into an 8 mL glass bottle, N-tert-butyloxycarbonyl-3-methyl-3-hydroxypiperidine (10.8 mg, 0.05 mmol), chiral ligand (S)-3,3'-bis(b-perfluoronaphthyl)-1,1'-binaphthol phosphate (3.4 mg, 0.004 mmol), sodium carbonate (0.8 mg, 0.008 mmol) and a stirrer were weighed in sequence. After nitrogen was replaced three times, isooctane (2 mL) and metal catalyst TiCl4 (0.19 mg, 0.001 mmol) were added under anhydrous and oxygen-free conditions. The reaction bottle was then sealed and placed in a temperature-controlled reaction tank (the temperature was set to 20 °C) and illuminated under a 395 nm LEDs lamp (light intensity 0.8 W / cm2 ) was subjected to light irradiation for 12 hours. After the light irradiation reaction was completed, the solvent was dried, and the crude product was purified by column chromatography and analyzed by HPLC to obtain (R)-N-tert-butyloxycarbonyl-3-methyl-3-hydroxypiperidine (9.8 mg, yield 91%, 98:2er). The absolute configuration of the product was confirmed by comparing the optical rotation signs.

[0229] 1 H NMR (400MHz, CDCl3) δ3.68–3.53(m,2H),3.03–2.92(m,2H),2.16(br,1H),1.77–1.62(m,2H),1.53–1.46(m,2H),1.43(s,9H),1.19(s,3H); 13 C NMR (100 MHz, CDCl3) δ 155.5, 79.7, 68.1, 54.9, 43.9, 37.2, 28.4, 26.5, 21.7; HRMS (ESI+): calculated value C 11 H 21 NO3Na + (M+Na) + 238.14136, measured value 238.14141; [α] D 25.0 +13.9 (c 1.0, CHCl3); HPLC analysis: ChiralPak ADH (n-hexane / i-PrOH=97 / 3, flow rate 1.0mL / min, λ=210nm), t R (major)=14.03min,t R (minor) = 15.14min.

[0230] Example 19 Preparation of (R)-N-tert-butyloxycarbonyl-3,5,5-trimethyl-3-hydroxypiperidine:

[0231]

[0232] Into an 8 mL glass bottle, N-tert-butyloxycarbonyl-3,5,5-trimethyl-3-hydroxypiperidine (12.2 mg, 0.05 mmol), chiral ligand (S)-3,3'-bis(b-perfluoronaphthyl)-1,1'-binaphthol phosphate (3.4 mg, 0.004 mmol), sodium carbonate (0.8 mg, 0.008 mmol) and a stirrer were weighed in sequence. After nitrogen was replaced three times, isooctane (2 mL) and metal catalyst TiCl4 (0.19 mg, 0.001 mmol) were added under anhydrous and oxygen-free conditions. The reaction bottle was then sealed and placed in a temperature-controlled reaction tank (the temperature was set to 20 °C) and illuminated under a 395 nm LEDs lamp (light intensity 0.8 W / cm2 ) was subjected to light irradiation for 12 hours. After the light irradiation reaction, the solvent was dried, and the crude product was purified by column chromatography and analyzed by HPLC to obtain (R)-N-tert-butyloxycarbonyl-3,5,5-trimethyl-3-hydroxypiperidine (11.5 mg, yield 94%, 95:5er). The absolute configuration of the product was confirmed by comparing the optical rotation signs.

[0233] 1 H NMR (400MHz, CDCl3) δ3.96–3.71(m,1H),3.63(d,J=13.2Hz,1H),2.86–2.62(m,1H),2.57(d,J=13.2Hz,1H),1 .86(br,1H),1.56(d,J=14.0Hz,1H),1.45(s,9H),1.30–1.24(m,1H),1.18(s,3H),1.09(s,3H),0.87(s,3H); 13 C NMR (100 MHz, CDCl3) δ 155.9, 79.6, 69.6, 55.7 & 54.5, 49.4, 31.7, 29.3, 28.8, 28.4, 26.2; HRMS (ESI+): calculated value C 13 H 25 NO3Na + (M+Na) + 266.17266, measured value 266.17313; [α] D 25.0 –6.2 (c 1.0, CHCl3); HPLC analysis: ChiralPak ADH (n-hexane / i-PrOH=97 / 3, flow rate 1.0mL / min, λ=210nm), t R (major)=11.26min,t R (minor) = 8.53min.

[0234] Example 20 Preparation of (1S, 2R)-2-(4-bromo-2-methoxyphenyl)cyclobutane-1-ol:

[0235]

[0236] Into an 8 mL glass bottle, trans-2-(4-bromo-2-methoxyphenyl)cyclobutan-1-ol (12.9 mg, 0.05 mmol), chiral ligand (R)-3,3'-bis(4-perfluorobiphenyl)-1,1'-binaphthol phosphate (7.8 mg, 0.008 mmol), sodium carbonate (1.6 mg, 0.015 mmol) and a stirrer were weighed in sequence. After nitrogen was replaced three times, isooctane (2 mL) and metal catalyst TiCl4 (0.38 mg, 0.002 mmol) were added under anhydrous and oxygen-free conditions. The reaction bottle was then sealed and placed in a temperature-controlled reaction tank (set to 20 °C) and illuminated under a 395 nm LEDs lamp (light intensity 0.8 W / cm 2 ) was photo-irradiated for 4 hours. After the photo-irradiation reaction, the solvent was dried, and the crude product was purified by column chromatography and analyzed by HPLC to obtain (1S, 2R)-2-(4-bromo-2-methoxyphenyl)cyclobutane-1-ol (10.4 mg, yield 81%, 8.9:1 d.r., 93:7 er). The absolute configuration of the product was confirmed by comparing the optical rotation signs.

[0237] 1 H NMR (400MHz, CDCl3) δ7.07(dd,J=8.0,2.0Hz,1H),6.98(d,J=2.0Hz,1H),6.96(dd,J=8.0,0.8Hz,1H),4.09–4.03(m,1H), 3.84(s,3H),3.39–3.33(m,1H),2.77(s,1H),2.26–2.19(m,1H),2.12–2.05(m,1H),1.96–1.86(m,1H),1.69–1.59(m,1H); 13 C NMR (100 MHz, CDCl3) δ 157.6, 130.4, 128.3, 123.7, 120.1, 113.7, 72.5, 55.8, 46.1, 28.2, 16.9; HRMS (EI+): calculated value C 11 H 13 BrO2 + (M) + 256.0093, measured value 256.0088; [α] D 25.0 –19.0 ​​(c 1.0, CHCl3); HPLC analysis: ChiralPak IH (n-hexane / i-PrOH=98 / 2, flow rate 1.0mL / min, λ=210nm), t R (major) = 19.44min, t R (minor) = 21.56min.

[0238] Example 21 Preparation of (1S, 2R)-2-ethyl-2-(4-methoxyphenyl)cyclobutan-1-ol:

[0239]

[0240] Into an 8 mL glass bottle, trans-2-ethyl-2-(4-methoxyphenyl)cyclobutan-1-ol (10.3 mg, 0.05 mmol), chiral ligand (R)-3,3'-bis(4-perfluorobiphenyl)-1,1'-binaphthol phosphate (3.9 mg, 0.004 mmol), sodium carbonate (0.8 mg, 0.008 mmol) and a stirrer were weighed in sequence. After nitrogen was replaced three times, n-heptane (4 mL) and metal catalyst TiCl4 (0.19 mg, 0.001 mmol) were added under anhydrous and oxygen-free conditions. The reaction bottle was then sealed and placed in a temperature-controlled reaction tank (the temperature was set to 0 °C) and illuminated under a 395 nm LEDs lamp (light intensity 0.8 W / cm 2 ) was subjected to light irradiation for 4 hours. After the light irradiation reaction, the solvent was dried, and the crude product was purified by column chromatography and analyzed by HPLC to obtain (1S, 2R)-2-ethyl-2-(4-methoxyphenyl)cyclobutan-1-ol (8.4 mg, yield 82%, 3:1 d.r., 90:10 er). The absolute configuration of the product was confirmed by the Mosher method, and the data analysis is as follows.

[0241] 1 H NMR (400MHz, CDCl3) δ7.25–7.22(m,2H),6.96–6.92(m,2H),4.08–4.02(m,1H),3.82(s,3H),2.44–2.36(m,1H),2.34 –2.28(m,1H),2.00–1.91(m,1H),1.73–1.64(m,1H),1.63–1.56(m,2H),1.28(d,J=9.6Hz,1H),0.59(t,J=7.2Hz,3H); 13 C NMR (100 MHz, CDCl3) δ 158.1, 131.6, 129.1, 113.9, 74.3, 55.2, 54.8, 35.0, 28.8, 23.2, 8.9; HRMS (ESI+): calculated value C 13 H 18 O2Na + (M+Na) + 229.11990, measured value 229.12051; [α] D 25.0+52.4 (c 1.0, CHCl3); HPLC analysis: ChiralPak IB (n-hexane / i-PrOH=95 / 5, flow rate 1.0mL / min, λ=210nm), t R (major)=8.70min,t R (minor) = 10.07min.

[0242] Derivatization of alcohols with (R)-(+)-MTPA: 1 H NMR (400 MHz, CDCl3) δ7.14 (d, J = 8.8 Hz, 10%), 7.02 (d, J = 8.8 Hz, 90%), 6.81 (d, J = 8.8 Hz, 10%), 6.69 (d, J = 8.8 Hz, 90%), 3.77 (s, 10%), 3.73 (s, 90%); Derivatization of alcohol with (S)-(–)-MTPA: 1 H NMR (400MHz, CDCl3) δ7.14 (d, J = 8.8 Hz, 90%), 7.02 (d, J = 8.8 Hz, 10%), 6.81 (d, J = 8.8 Hz, 90%), 6.69 (d, J = 8.8 Hz, 10%), 3.77 (s, 90%), 3.73 (s, 10%).

[0243] Example 22 Preparation of (1R, 2S)-2-phenylcycloheptyl-1-ol:

[0244]

[0245] Into an 8 mL glass bottle, trans-2-phenylcycloheptyl-1-ol (9.5 mg, 0.05 mmol), chiral ligand (R)-3,3'-bis(4-perfluorobiphenyl)-1,1'-binaphthol phosphate (7.8 mg, 0.008 mmol), sodium carbonate (1.6 mg, 0.015 mmol) and a stirrer were weighed in sequence. After nitrogen was replaced three times, isooctane (2 mL) and metal catalyst TiCl4 (0.38 mg, 0.002 mmol) were added under anhydrous and oxygen-free conditions. The reaction bottle was then sealed and placed in a temperature-controlled reaction tank (the temperature was set to 20 °C) and illuminated under a 395 nm LEDs lamp (light intensity 0.8 W / cm 2) was subjected to light irradiation for 12 hours. After the light irradiation reaction, the solvent was dried, and the crude product was purified by column chromatography and analyzed by HPLC to obtain (1R, 2S)-2-phenylcycloheptyl-1-ol (8.1 mg, yield 85%, 10:1 d.r., 90:10 er). The absolute configuration of the product was confirmed by comparing the optical rotation sign with that of the known literature (J.Am.Chem.Soc.2014,136,17591-17600), and the optical rotation sign of (1R,2S) was positive.

[0246] 1 H NMR (400MHz, CDCl3) δ7.36–7.31(m,2H),7.25–7.21(m,3H),3.81–3.75(m, 1H),2.59–2.53(m,1H),2.07–2.00(m,1H),1.85–1.55(m,9H),1.43(s,1H); 13 C NMR (100 MHz, CDCl3) δ 145.8, 128.8, 127.7, 126.6, 77.6, 55.4, 35.3, 32.1, 27.4, 26.8, 21.9; HRMS (EI+): calculated value C 13 H 16 + (M–H2O) + 172.1247, measured value 172.1246; [α] D 25.0 +3.0 (c 1.0, CHCl3); HPLC analysis: ChiralPak ADH (n-hexane / i-PrOH=97 / 3, flow rate 1.0mL / min, λ=210nm), t R (major)=15.90min,t R (minor) = 14.03min.

[0247] Example 23 Preparation of N-((1R, 2S)-2-hydroxy-1,2-diphenylethyl)-4-methylbenzenesulfonamide:

[0248]

[0249] Into an 8 mL glass bottle, trans-N-(2-hydroxy-1,2-diphenylethyl)-4-methylbenzenesulfonamide (18.4 mg, 0.05 mmol), chiral ligand (4R,4'R,5S,5'S)-2,2'-(1,3-diphenylpropane-2,2-diyl)bis(4,5-diphenyl-4,5-dihydrooxazole) (3.2 mg, 0.005 mmol), sodium carbonate (1.6 mg, 0.015 mmol) and a stirrer were weighed in sequence. After nitrogen was replaced three times, dichloromethane (0.25 mL) and metal catalyst TiCl4 (0.38 mg, 0.002 mmol) were added under anhydrous and oxygen-free conditions. The reaction bottle was then sealed and placed in a temperature-controlled reaction tank (the temperature was set to 20 ° C) and illuminated under a 395 nm LEDs lamp (light intensity 0.8 W / cm 2 ) was photo-irradiated for 4 hours. After the photo-irradiation reaction, the solvent was dried, and the crude product was purified by column chromatography and HPLC analysis to separate the chiral amino alcohol N-((1R,2S)-2-hydroxy-1,2-diphenylethyl)-4-methylbenzenesulfonamide (17.5 mg, yield 95%, 20:1 d.r., 98:2 er). The absolute configuration of the product was confirmed by single crystal X-ray diffraction. The single crystal diffraction pattern is shown in Figure 1 .

[0250] The XRD characterization data of the product is CCDC:2266206.

[0251] Crystallographic data and structural modification of the product

[0252]

[0253]

[0254] 1 H NMR (400MHz, DMSO-d6) δ8.11(d,J=9.2Hz,1H),7.31(d,J=8.0Hz,2H),7.20–7.18(m,3H),7.14–7.12(m,2H),7. 07–7.03(m,7H),5.38(d,J=4.8Hz,1H),4.63(dd,J=6.8,4.8Hz,1H),4.30(dd,J=9.6,6.8Hz,1H),2.26(s,3H); 13 C NMR (100 MHz, DMSO-d6) δ 142.7, 141.7, 138.9, 138.6, 128.9, 128.3, 127.6, 127.1, 127.0, 126.8, 126.4, 126.2, 75.4, 63.4, 20.9; HRMS (ESI+): calculated value C 21 H 21NO3NaS + (M+Na) + 390.11344, measured value 390.11331; [α] D 25.0 +63.3 (c 0.1, THF); HPLC analysis: ChiralPak IB (n-hexane / i-PrOH=80 / 20, flow rate 1.0 mL / min, λ=240 nm), t R (major)=13.63min,t R (minor) = 15.99min.

[0255] Example 24 Preparation of N-((1R, 2S)-2-(4-bromophenyl)-2-hydroxy-1-phenylethyl)-4-methylbenzenesulfonamide:

[0256]

[0257] Into an 8 mL glass bottle, trans-N-2-(4-bromophenyl)-2-hydroxy-1-phenylethyl)-4-methylbenzenesulfonamide (22.3 mg, 0.05 mmol), chiral ligand (4R, 4'R, 5S, 5'S)-2,2'-(1,3-diphenylpropane-2,2-diyl)bis(4,5-diphenyl-4,5-dihydrooxazole) (6.4 mg, 0.01 mmol), sodium carbonate (1.6 mg, 0.015 mmol) and a stirrer were weighed in sequence. After nitrogen was replaced three times, dichloromethane (0.25 mL) and metal catalyst TiCl4 (0.76 mg, 0.004 mmol) were added under anhydrous and oxygen-free conditions. The reaction bottle was then sealed and placed in a temperature-controlled reaction tank (the temperature was set to 20 ° C) and illuminated under a 395 nm LEDs lamp (light intensity 0.8 W / cm 2 ) was subjected to light irradiation for 4 hours. After the light irradiation reaction, the solvent was dried, and the crude product was purified by column chromatography and analyzed by HPLC to separate N-((1R, 2S)-2-(4-bromophenyl)-2-hydroxy-1-phenylethyl)-4-methylbenzenesulfonamide (21.2 mg, yield 95%, 16:1 d.r., 99:1 er). The absolute configuration of the product was confirmed by comparing the optical rotation symbol with that of Example 23.

[0258] 1H NMR (400MHz, DMSO-d6) δ8.19(d,J=9.6Hz,1H),7.33(d,J=8.4Hz,2H),7.25(d,J=8.4Hz,2H),7.11–7.10(m,6H), 7.08–7.05(m,3H),5.47(d,J=4.8Hz,1H),4.55(dd,J=7.6,5.2Hz,1H),4.21(dd,J=9.6,7.6Hz,1H),2.29(s,3H); 13 C NMR (100 MHz, DMSO-d6) δ 142.3, 141.7, 139.6, 138.5, 130.4, 129.0, 128.9, 128.2, 127.3, 126.6, 126.1, 120.2, 74.7, 63.2, 21.0; HRMS (ESI+): calculated value C 21 H 20 NO3NaSBr + (M+Na) + 468.02395, measured value 468.02454; [α] D 25.0 +53.5 (c 0.1, THF); HPLC analysis: ChiralPak IB (n-hexane / i-PrOH=80 / 20, flow rate 1.0mL / min, λ=240nm), t R (major)=14.61min,t R (minor) = 15.40min.

[0259] Example 25 Preparation of N-((1R, 2S)-2-hydroxy-1-(4-methoxyphenyl)-2-phenylethyl)-4-methylbenzenesulfonamide:

[0260]

[0261] Into an 8 mL glass bottle, trans-N-2-hydroxy-1-(4-methoxyphenyl)-2-phenylethyl)-4-methylbenzenesulfonamide (19.9 mg, 0.05 mmol), chiral ligand (4R, 4'R, 5S, 5'S)-2,2'-(1,3-diphenylpropane-2,2-diyl)bis(4,5-diphenyl-4,5-dihydrooxazole) (3.2 mg, 0.005 mmol), sodium carbonate (1.6 mg, 0.015 mmol) and a stirrer were weighed in sequence. After nitrogen was replaced three times, dichloromethane (0.25 mL) and metal catalyst TiCl4 (0.38 mg, 0.002 mmol) were added under anhydrous and oxygen-free conditions. The reaction bottle was then sealed and placed in a temperature-controlled reaction tank (the temperature was set to 20 ° C) and illuminated under a 395 nm LEDs lamp (light intensity 0.8 W / cm 2 ) was subjected to light irradiation for 4 hours. After the light irradiation reaction, the solvent was dried, and the crude product was purified by column chromatography and analyzed by HPLC to separate N-((1R, 2S)-2-hydroxy-1-(4-methoxyphenyl)-2-phenylethyl)-4-methylbenzenesulfonamide (18.7 mg, yield 94%, 20:1 d.r., 98:2 er). The absolute configuration of the product was confirmed by comparing the optical rotation symbol with that of Example 23.

[0262] 1 H NMR (400MHz, DMSO-d6) δ8.01(d,J=9.2Hz,1H),7.31(d,J=8.4Hz,2H),7.22–7.17(m,3H),7.13–7.11(m,2H),7.07(d,J=8.0Hz,2H),6.91(d,J= 8.8Hz,2H),6.59(d,J=8.8Hz,2H),5.34(d,J=4.8Hz,1H),4.63(dd,J=6.4,4.8Hz,1H),4.25(dd,J=9.2,6.4Hz,1H),3.65(s,3H),2.27(s,3H); 13 C NMR (100 MHz, DMSO-d6) δ 158.0, 142.8, 141.6, 138.7, 130.7, 129.4, 128.9, 127.6, 126.9, 126.7, 126.3, 112.5, 75.4, 62.9, 54.9, 20.9; HRMS (ESI+): calculated value C 22 H 23 NO4NaS + (M+Na) + 420.12400, measured value 420.12293; [α] D 25.0+48.9 (c 0.1, THF); HPLC analysis: ChiralPak IB (n-hexane / i-PrOH=80 / 20, flow rate 1.0 mL / min, λ=240 nm), t R (major) = 17.99min, t R (minor) = 21.23min.

[0263] Comparative Example 1 Condition Screening of Cycloalcohol

[0264] With reference to the experimental operation and test method of Example 1, the following parameters were used to screen the reaction parameters.

[0265] 1. Chiral ligand screening

[0266]

[0267] 2. Titanium source screening

[0268]

[0269] 3. Catalyst equivalent screening

[0270]

[0271] 4. Reaction time test

[0272]

[0273] 5. Light intensity screening

[0274]

[0275] 6. Screening of alkali

[0276]

[0277] 7.Solvent screening

[0278]

[0279] 8. Temperature screening

[0280]

[0281] 9. Controlled Experiments

[0282]

[0283] Comparative Example 2: Condition screening of amino alcohols

[0284] Referring to the experimental operation and detection method of Example 23, the reaction parameters of the amino alcohol substrate were screened.

[0285] 1. Chiral ligand screening

[0286]

[0287] 2. Catalyst equivalent screening

[0288]

[0289] 3. Alkali screening

[0290]

[0291] 4. Control Experiment

[0292]

Claims

1. A method for preparing a chiral alcohol compound, comprising the following steps: In a solvent, under light and anhydrous conditions, a non-chiral alcohol compound is reacted in the presence of a titanium catalyst, a ligand and a base to obtain a chiral alcohol compound; The preparation method is the following method 1, method 2 or method 3: Method 1: The achiral alcohol compound is a compound as shown in Formula I, and the chiral alcohol compound is a compound as shown in Formula I-1, a compound as shown in Formula I-2, a compound as shown in Formula I-3, or a compound as shown in Formula I-4; Method 2: The achiral alcohol compound is a compound as shown in formula II, and the chiral alcohol compound is a compound as shown in formula II-1 or a compound as shown in formula II-2; Method 3: The achiral alcohol compound is a compound of formula III, and the chiral alcohol compound is a compound of formula III-1 or a compound of formula III-2; Wherein, Ring A is a 4-20-membered cycloalkyl, a 4-10-membered heterocycloalkyl or a 6-10-membered heteroaryl; the heteroatoms in the 4-10-membered heterocycloalkyl are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatoms in the 6-10-membered heteroaryl are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3; Ring B is a 4-20 membered heterocycloalkyl group; the heteroatoms in the 4-20 membered heterocycloalkyl group are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3; R 1 is unsubstituted or one or more R 1-0 Substituted C1-C6 alkyl, unsubstituted or one or more R 1-1 substituted 6-10 membered aryl, or unsubstituted or one or more R 1-2 A substituted 6-10 membered heteroaryl group, wherein the heteroatoms in the 6-10 membered heteroaryl group are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3; R 2 is hydrogen or unsubstituted or one or more R 2-1 Substituted C1-C6 alkyl; R 3 and R 4 Each independently is unsubstituted or one or more R 3-1 Substituted 6-10 membered aryl; R 5 is an amino protecting group; R 6 is hydrogen, unsubstituted or one or more R 6-1 Substituted C1-C6 alkyl or unsubstituted or one or more R 6-2 Substituted 6-10 membered aryl; R 7 and R 8 is unsubstituted or one or more R 8-1 Substituted C1-C6 alkyl, unsubstituted or one or more R 8-2 A substituted 6-10 membered aryl group, or an amino protecting group; m and n are each independently 0, 1, 2 or 3; R 1-0 , R 1-1 , R 1-2 , R 2-1 , R 3-1 , R 6-1 , R 6-2 , R 8-1 and R 8-2 Each independently is halogen, unsubstituted or one or more R 1 -1-1 Substituted C1-C6 alkyl, unsubstituted or one or more R 1-1-2 Substituted C1-C6 alkoxy, unsubstituted or one or more R 1-1-3 Substituted C1-C6 alkylthio; R 1-1-1 , R 1-1-2 and R 1-1-3 are each independently a halogen; The titanium catalyst is one or more of titanium tetrachloride, titanium tetrabromide, tetraisopropoxytitanium and biscyclopentadienyltitanium dichloride; The ligand is a chiral bisoxazoline ligand, The wavelength of the light is 360-400nm.

2. The preparation method according to claim 1, characterized in that It meets one or more of the following conditions: (1) Each of the C1-C6 alkane groups is independently a C1-C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or ethyl; (2) each of the C1-C6 alkoxy groups is independently a C1-C4 alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy; (3) Each of the C1-C6 alkylthio groups is independently a C1-C4 alkylthio group, such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio or tert-butylthio, preferably methylthio; (4) Each of the halogens is F, Cl, Br or I, preferably F, Cl or Br; (5) Each of the 6-10 membered aryl groups is phenyl or naphthyl; (6) Each of the 6-10 membered heteroaryl groups is a 9-10 membered heteroaryl group, the heteroatom is selected from one of N, O and S, and the number of heteroatoms is 1, such as phenylpropyloxyhexyl, benzofuranyl or benzothiopheneyl; (7) Each of the 4-20-membered cycloalkyl groups is a 4-15-membered cycloalkyl group, preferably a 4-7-membered cycloalkyl group, such as cyclobutane, cyclopentane, cyclohexane or cycloheptane; (8) Each of the 4-10 membered heterocycloalkyl groups is a 4-6 membered heterocycloalkyl group, wherein the heteroatom is selected from one of N, O and S, and the number of the heteroatom is 1, such as cyclopentyl, cyclohexyl, azetidinyl, azocyclopentyl, azohexyl; most preferably, it is a 6 membered heterocycloalkyl group, wherein the heteroatom is selected from one of N, O and S, and the number of the heteroatom is 1, such as cyclohexyl or azohexyl; (9) Each amino-protecting group is tert-butyloxycarbonyl.

3. The preparation method according to claim 1, characterized in that: It meets one or more of the following conditions: (1) Ring A is a 4-20 membered cycloalkyl or a 4-10 membered heterocycloalkyl, preferably a 4-20 membered cycloalkyl; the heteroatom in the 4-10 membered heterocycloalkyl is selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3; the heteroatom in the 4-10 membered heterocycloalkyl is preferably selected from one of N, O and S, and the number of heteroatoms is 1; (2)R 1 is unsubstituted or one or more R 1-1 A substituted 6-10 membered aryl group, or an unsubstituted 6-10 membered heteroaryl group, wherein the heteroatoms in the 6-10 membered heteroaryl group are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3; the 6-10 membered aryl group is preferably phenyl or naphthyl; (3)R 2 is hydrogen or unsubstituted C1-C6 alkyl; (4)R 3 and R 4 Each independently is unsubstituted or one or more R 3-1 Substituted 6-10 membered aryl; (5)R 6 is hydrogen, unsubstituted C1-C6 alkyl or unsubstituted or one or more R 6-2 Substituted 6-10 membered aryl; (6)R 7 is an amino protecting group; (7)R 8 is an unsubstituted C1-C6 alkyl or amino protecting group; (8) In ring A, when the heterocycloalkyl group or heterocycloaryl group contains a N atom, an amino protecting group is attached to the N atom; (9) In ring B, when the heterocycloalkyl group contains a N atom, an amino protecting group is attached to the N atom; R 1-1 is halogen, unsubstituted or one or more R 1-1-1 Substituted C1-C6 alkyl, unsubstituted or one or more R 1-1-2 Substituted C1-C6 alkoxy, unsubstituted C1-C6 alkylthio; (10)R 3-1 It is halogen, unsubstituted C1-C6 alkoxy.

4. The preparation method according to claim 1, characterized in that: It meets one or more of the following conditions: (1) Ring A is cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopentane, cyclohexane, azetidinyl, azopentane or phenylcyclohexane; (2) Ring B is oxirane, azocyclopentane or azocyclohexane; preferably azocyclohexane; (3)R 1-1 is fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy, trifluoromethoxy, methylthio; R 2 is hydrogen or ethyl; (4)R 3-1 is bromine or methoxy; (5)R 7 is tert-butyloxycarbonyl; (6)R 8 is methyl or tert-butyloxycarbonyl; (7) m is 0, 1 or 3; (8)n is 0 or 1.

5. The preparation method according to claim 1, characterized in that: It meets one or more of the following conditions: (1) In the compound shown in Formula I, Ring A is A end is connected to the hydroxyl group; preferably Preferably, in the compound as shown in Formula I, Ring A is The a end is connected to the hydroxyl group; preferably (2) In the compound shown in formula III, ring B is Best (3)R 1 is phenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4-chlorophenyl, 2-methylphenyl, 3-methylthiophenyl, 4-fluorophenyl, 3-trifluoromethylphenyl, 4-bromo-2-methoxyphenyl, b-naphthyl, 6-benzofuranyl or 5-benzothiophenyl; (4)R 3 is phenyl or 4-bromophenyl; (5)R 4 is phenyl or 4-methoxyphenyl; (6)R 5 is 4-methylbenzenesulfonyl; (7)R 6 It is hydrogen, methyl, phenyl, 3-trifluoromethylphenyl, 2-methoxy-3-fluorophenyl.

6. The preparation method according to claim 1, characterized in that: It meets one or more of the following conditions: (1) The compound represented by Formula I is a compound represented by Formula 1, a compound represented by Formula 2, a compound represented by Formula 3 or a compound represented by Formula 4; preferably, the compound represented by Formula 1, the compound represented by Formula 2 or the compound represented by Formula 3; (2) The compound represented by Formula II is a compound represented by Formula 5 or a compound represented by Formula 6; preferably, the compound represented by Formula 5; (3) The compound represented by Formula III is a racemic compound, that is, the molar ratio of the compound represented by Formula 7 to the compound represented by Formula 8 is 1:1; 7. The preparation method according to claim 6, characterized in that: It meets one or more of the following conditions: (1) The compound represented by Formula 1 is cis-2-phenylcyclopentan-1-ol, cis-2-(4-methoxyphenyl)cyclopentan-1-ol, cis-2-(4-trifluoromethoxyphenyl)cyclopentan-1-ol, cis-2-(4-chlorophenyl)cyclopentan-1-ol, cis-2-(2-methylphenyl)cyclopentan-1-ol, cis-2-(3-methylthiophenyl)cyclopentan-1-ol, cis-2-(b-naphthyl)cyclopentan-1-ol or cis-2-(5-benzothiophenyl)cyclopentan-1-ol; (2) The compound represented by formula 2 is trans-2-phenylcyclohexan-1-ol, trans-2-(4-methoxyphenyl)cyclohexan-1-ol, trans-2-(4-fluorophenyl)cyclohexan-1-ol, trans-2-(3-trifluoromethylphenyl)cyclohexan-1-ol, trans-2-(6-benzofuranyl)cyclohexan-1-ol, trans-2-phenylcycloheptan-1-ol; (3) The compound shown in Formula 3 is trans-2-(4-bromo-2-methoxyphenyl)cyclobutan-1-ol or trans-2-ethyl-2-(4-methoxyphenyl)cyclobutan-1-ol; (4) the compound represented by Formula 5 is trans-N-(2-hydroxy-1,2-diphenylethyl)-4-methylbenzenesulfonamide, trans-N-2-(4-bromophenyl)-2-hydroxy-1-phenylethyl)-4-methylbenzenesulfonamide or trans-N-2-hydroxy-1-(4-methoxyphenyl)-2-phenylethyl)-4-methylbenzenesulfonamide; (5) The compound represented by formula III is 1-tert-butoxycarbonyl-3-hydroxypiperidine, N-tert-butoxycarbonyl-3-phenylpiperidin-3-ol, N-tert-butoxycarbonyl-3-(3-trifluoromethylphenyl)piperidin-3-ol, N-tert-butoxycarbonyl-3-(2-methoxy-3-fluorophenyl)piperidin-3-ol, N-tert-butoxycarbonyl-3-methyl-3-hydroxypiperidine or N-tert-butoxycarbonyl-3,5,5-trimethyl-3-hydroxypiperidine.

8. The preparation method according to claim 1, characterized in that: It meets one or more of the following conditions: (1) The compound represented by formula I-1 is selected from any one of the following compounds: (2) The compound represented by formula I-2 is selected from any one of the following compounds: (3) The compound represented by formula I-3 is selected from any one of the following compounds: (4) The compound represented by formula II-1 is selected from any one of the following compounds: (5) The compound shown in formula III-1 is the following compound: (6) The compound represented by formula III-2 is selected from any one of the following compounds:

9. The preparation method according to claim 1, characterized in that: It meets one or more of the following conditions: (1) The chiral bisoxazoline ligand is Best (2) In the method for preparing the chiral alcohol compound, the titanium catalyst is one or more of titanium tetrachloride, titanium tetrabromide and titanium tetraisopropoxide, preferably titanium tetrachloride and / or titanium tetrabromide, more preferably titanium tetrachloride; (3) In the method for preparing the chiral alcohol compound, the base is an inorganic base and / or an organic base; the inorganic base is preferably one or more of sodium carbonate, potassium carbonate, lithium carbonate, sodium phosphate and lithium phosphate, more preferably sodium carbonate; the organic base is preferably one or more of diisopropylethylamine, 2,6-lutidine and 2,4,6-trimethylpyridine, more preferably diisopropylethylamine; (4) In the method for preparing the chiral alcohol compound, the solvent is one or more of an alkane solvent, a halogenated hydrocarbon solvent and an aromatic hydrocarbon solvent; the alkane solvent is preferably a chain alkane solvent and / or a cycloalkane solvent, the chain alkane is preferably one or more of n-hexane, n-heptane and isooctane, the cycloalkane solvent is preferably cyclohexane; the halogenated hydrocarbon solvent is preferably dichloromethane and / or chloroform; the aromatic hydrocarbon solvent is preferably toluene; (5) In the method for preparing the chiral alcohol compound, the molar ratio of the titanium catalyst to the achiral alcohol compound is a conventional molar ratio for such reactions in the art, for example, 0.001 to 0.5:1, preferably 0.005 to 0.2:1, more preferably 0.005 to 0.1:1, and most preferably 0.01:1, 0.02:1, 0.04:1 or 0.08:1; (6) In the method for preparing the chiral alcohol compound, the molar ratio of the ligand to the achiral alcohol compound is a conventional molar ratio for such reactions in the art, such as 0.001 to 1:1, preferably 0.005 to 0.6:1, more preferably 0.005 to 0.3:1, such as 0.01:1, 0.02:1, 0.04:1, 0.08:1, 0.12:1 or 0.16:1, most preferably 0.01:1, 0.02:1, 0.08:1 or 0.16:1; (7) In the method for preparing the chiral alcohol compound, the molar ratio of the base to the achiral alcohol compound is a conventional molar ratio for such reactions in the art, such as 0.001 to 1:1, preferably 0.01 to 0.6:1, more preferably 0.04 to 0.3:1, such as 0.04:1, 0.08:1, 0.12:1, 0.16:1 or 0.3:1, most preferably 0.16:1 or 0.3:1; (8) In the method for preparing the chiral alcohol compound, the molar ratio of the base to the ligand is a conventional molar ratio for such reactions in the art, for example, 1 to 5:1, preferably 1 to 3:1, more preferably 1.5:1, 1.875:1, 2:1 or 3:1; (9) In the method for preparing the chiral alcohol compound, the molar concentration of the achiral alcohol compound is the molar concentration conventional in this type of reaction in the art, for example, 0.005 to 0.5 mol / L, preferably 0.01 to 0.1 mol / L, more preferably 0.01 to 0.05 mol / L, and most preferably 0.025 mol / L; (10) In the method for preparing the chiral alcohol compound, the wavelength of the light is 365-395 nm, for example 365 nm or 395 nm, preferably 395 nm; (11) In the method for preparing the chiral alcohol compound, the light intensity of the illumination is 0.02-2.00 W / cm 2 , preferably 0.05-1.80W / cm 2 , for example 0.1W / cm 2 , 0.2W / cm 2 , 0.4W / cm 2 、0.6W / cm 2 or 1.6W / cm 2 , preferably 0.8W / cm 2 ; (12) In the method for preparing the chiral alcohol compound, the reaction temperature is a conventional reaction temperature for such reactions in the art, for example, -60 to 30°C, preferably -40 to 20°C, for example, 0°C, 20°C, most preferably 0°C or 20°C; (13) The method for preparing the chiral alcohol compound is carried out under aerobic or anaerobic conditions, preferably under anaerobic conditions; (14) In the method for preparing the chiral alcohol compound, the reaction time is the conventional reaction time for this type of reaction in the art, for example, 2 to 72 hours, preferably 4 to 48 hours, more preferably 4 hours, 6 hours, 12 hours, 18 hours, 24 hours or 48 hours.

10. The preparation method according to claim 1, characterized in that: It meets one or more of the following conditions: (1) In the method for preparing the chiral alcohol compound, when the compound shown in formula I is The ligand is When the product of the method 1 is (2) In the method for preparing the chiral alcohol compound, when the compound shown in Formula I is The ligand is When the product of the method 1 is (3) In the method for preparing the chiral alcohol compound, when the compound shown in Formula I is The ligand is When the product of the method 1 is (4) In the method for preparing the chiral alcohol compound, when the compound shown in Formula I is The ligand is When the product of the method 1 is (5) In the method for preparing the chiral alcohol compound, when the compound shown in Formula II is The ligand is a chiral bisoxazoline ligand, and the chiral bisoxazoline ligand is When the product of the second method is (6) In the method for preparing the chiral alcohol compound, when the compound shown in Formula II is The ligand is a chiral bisoxazoline ligand, and the chiral bisoxazoline ligand is When the product of the second method is (7) In the method for preparing the chiral alcohol compound, in method 3, when R 6 is hydrogen, and the ligand is When the product of the method three is (8) In the method for preparing the chiral alcohol compound, in method 3, when R 6 is unsubstituted or one or more R 6-1 Substituted C1-C6 alkyl or unsubstituted or one or more R 6-2 substituted 6-10 membered aryl, the ligand is When the product of the method three is (9) In the method for preparing the chiral alcohol compound, in the method 1, the base is one or more of sodium carbonate, lithium carbonate, sodium phosphate and diisopropylethylamine, preferably one or more of sodium carbonate, lithium carbonate and sodium phosphate; (10) In the method for preparing the chiral alcohol compound, in the method 2, the base is one or more of sodium carbonate, potassium carbonate, lithium phosphate, diisopropylethylamine and 2,4,6-trimethylpyridine, preferably sodium carbonate and / or potassium carbonate; In the method for preparing the chiral alcohol compound, in method three, the base is sodium carbonate.

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