Synthesis method of homoallylamine

Abstract

The invention relates to a method for synthesizing homoallylamine, which comprises the following step: by taking an amino-unprotected primary amine compound and an allylation reagent as raw materials, reacting under the catalysis of a carbonyl catalyst and a metal catalyst to obtain the homoallylamine. Compared with the prior art, the method has the advantages that by means of carbonyl catalysis and strong catalytic capability, unprotected primary amine can be directly catalyzed to perform corresponding conversion, introduction and removal of a protecting group are avoided, a synthesis route is shortened, and pollution is reduced.

Description

Technical Field

[0001] The present invention belongs to the technical field of organocatalysis and relates to a method for synthesizing homoallylic amines. Background Art

[0002] Chiral amines are widely present in various natural products, bioactive molecules, drugs, materials, and catalysts, thus greatly promoting the development of innovative methods for synthesizing chiral amines. Transition-metal-catalyzed asymmetric allylic amination is a well-established method for constructing new compounds in organic synthesis and can serve as a reliable platform for producing chiral amines. Primary amine compounds mainly include various activated primary amines, such as amino acids, etc.; weakly activated primary amines, such as benzylamine, etc.; and unactivated primary amines, such as alkylamines, etc., which are all common chemical raw materials. They act as excellent N-nucleophiles in the transition-metal-catalyzed allylic substitution reaction to form amine compounds, among which the alkylamine substrate has the highest attacking activity at the amino group. However, if the allylic substitution occurs at the C-H bond of the amino group α-position of any primary amine, especially alkyl primary amine, it will provide a general, simple, and efficient strategy for synthesizing chiral homoallylic amines. These molecules not only have biological significance but also can serve as powerful building blocks for constructing nitrogen-containing compounds. However, due to the very low acidity (pK a ~57) of the C-H bond at the α-position of the amino group of alkyl primary amines, it is very difficult to deprotonate it into an active nucleophilic carbanion. In addition, the unprotected NH2 group will seriously interfere with the α-position C-H allylic alkylation process. So far, only the allylation reactions of protected primary amines (Niu, J. Am. Chem. Soc. 2016, 138, 13103 - 13106; Wang, Adv. Syn. Catal. 2018, 360, 4715 - 4719; Zhang, Chem. Commun. 2018, 54, 599 - 602; Zhang, Org. Lett. 2020, 22, 5479 - 5485; Wang, Angew. Chem. Int. Ed. 2022, 61, e02212948; Yin, Nat. Commun., 2023, 14, 2187) and unprotected amino acid esters (Guo, J. Am. Chem. Soc. 2019, 141, 5159 - 5163; Guo, Tetrahedron, 2023, 132, 133215) have been reported, and no general method for directly using unprotected primary amines as raw materials to prepare the corresponding homoallylic amine compounds has been seen. Summary of the Invention

[0003] The object of the present invention is to provide a method for synthesizing homoallylamine, which can directly catalyze the corresponding transformation of unprotected primary amines, avoiding the introduction and removal of protecting groups, shortening the synthesis route, and reducing pollution.

[0004] The object of the present invention can be achieved by the following technical solutions:

[0005] A method for synthesizing homoallylamine, using an unprotected primary amine compound and an allylation reagent as raw materials, and reacting under the catalysis of a carbonyl catalyst and a metal catalyst to obtain homoallylamine.

[0006] The chemical equation for the entire synthesis route process can be:

[0007]

[0008] Furthermore, the structure of the unprotected primary amine compound is:

[0009]

[0010] Wherein, R 1 is selected from any one of alkyl, substituted alkyl substituted with any number of substituents, cycloalkyl containing at least one heteroatom in the ring, substituted aryl substituted with any number of substituents, substituted heteroaryl substituted with any number of substituents, substituted alkenyl substituted with any number of substituents, and substituted alkenyl substituted with any number of substituents.

[0011] Even further, the substituents in R 1 are selected from halogen, C1-C10 alkyl, C1-C10 alkoxy, aryl, haloalkyl, nitro, alkoxycarbonyl, amido, ketocarbonyl, aldehyde group, protected or unprotected hydroxyl group, protected or unprotected amino group; the heteroatom is selected from O, S, NH or NRp, and Rp is an amino protecting group.

[0012] Furthermore, the structure of the allylation reagent is:

[0013]

[0014] Wherein, R 2 , R 3 , R 4 are independently selected from H, aryl, substituted aryl or heteroaryl substituted with any number of Rn, alkyl alkenyl, and substituted alkyl alkenyl substituted with any number of Rn;

[0015] Rn is selected from any one of halogen, C1-C10 alkyl, C1-C10 alkoxy, aryl, haloalkyl, and nitro;

[0016] The heteroatom of the heteroaryl group is selected from O, S, NH or NRp, where Rp is an amino protecting group;

[0017] PG is selected from tert-butoxycarbonyl, benzyloxycarbonyl, ethyloxycarbonyl, methyloxycarbonyl, acetyl, phosphate group.

[0018] Furthermore, the carbonyl catalyst is 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0019] Furthermore, the metal catalyst is any one of [Ir(COD)Cl]2, Ir(COD)2BF4, Ir(acac)(CO)2, [Ir(CH2CH2)2Cl]2, Ir(PPh3)2(CO)Cl, [Ir(COD)(OMe)]2, [Ir(COE)2Cl]2, [Ir(acac)(COD)], or [Ir(hfac)(COD)].

[0020] Furthermore, the molar ratio of the allylation reagent, the primary amine compound with unprotected amino group, the carbonyl catalyst, and the metal catalyst is 1:(0.50 - 5.0):(0.01 - 0.20):(0.01 - 0.10). Specifically, it can be 1:0.5:0.01:0.01, 1:5:0.20:0.10, or any intermediate value within this range such as 1:2:0.1:0.05.

[0021] Furthermore, a ligand is added during the reaction, and its molar ratio with the allylation reagent is (0.01 - 0.2):1. Specifically, it can be 0.01:1, 0.2:1, or any intermediate value within this range such as 0.1:1. It is selected from any one of the following structures:

[0022]

[0023]

[0024] and its enantiomeric structure;

[0025] wherein, R 5 or R 7 is independently a substituted or unsubstituted C4 - C 15 aryl group, and the substituents include C1 - C8 alkyl group, C4 - C 15 aryl group, protected amino group, hydroxyl group, halogen, nitro group, cyano group;

[0026] R 6 is independently selected from cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cyclotetradecyl, cyclopentadecyl, cyclohexadecyl, diphenylmethyl, dicyclohexylmethyl.

[0027] Further, an alkali is added during the reaction, and the molar ratio of the alkali to the allylation reagent is (0.10 - 5.00):1. Specifically, it can be 0.1:1, 5:1, or any intermediate value within this range such as 2:1. The alkali is at least one of sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, calcium hydride, potassium fluoride, triethylamine, diisopropylamine, diisopropylethylamine, tetramethylethylenediamine, N,N-dimethylaniline, N,N-diethylaniline, 1,4-diazabicyclooctane (DABCO), tetramethylguanidine (TMG), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), n-butyllithium, 1,4-dimethylpiperazine, 1-methylpiperidine, 1-methylpyrrole, quinoline, or pyridine.

[0028] Further, an additive is added during the reaction, and it is selected from any one of zinc fluoride, zinc chloride, zinc bromide, zinc iodide, zinc phosphate, zinc hydroxide, zinc carbonate, zinc benzoate, zinc trifluoroacetate, zinc p-toluenesulfonate, silver trifluoromethanesulfonate, copper trifluoromethanesulfonate, iron trifluoromethanesulfonate, scandium trifluoromethanesulfonate, calcium bromide, copper bromide, cuprous bromide, iron bromide, or magnesium bromide.

[0029] Furthermore, the molar ratio of the additive to the allylation reagent is (0.10 - 5.00):1. Specifically, it can be 0.1:1, 5:1, or any intermediate value within this range such as 2:1.

[0030] Further, the reaction is carried out in a solvent system, and the solvents used are at least one of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, cyclohexyl methyl ether, ethylene glycol dimethyl ether, ethylene glycol monomethyl ether, water, methanol, ethanol, n-propanol, isopropanol, n-butanol, trifluoroethanol, benzene, toluene, xylene, mesitylene, acetonitrile, dichloromethane, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone.

[0031] Further, the reaction temperature is 0 - 50 °C and the time is 1 - 72 h. Specific Embodiments

[0032] The present invention will be described in detail below with reference to specific embodiments. These embodiments are implemented on the premise of the technical solution of the present invention, and detailed implementation manners and specific operation processes are given. However, the protection scope of the present invention is not limited to the following embodiments.

[0033] In the following examples, allyl carbonate was synthesized according to the published literature (Journal of the American Chemical Society 2011, 133, 8165 - 8167), and both the ligand and the metal catalyst were commercially available products (Strem Chemicals, Inc.).

[0034] For the remaining raw materials or processing techniques without special instructions, they are all conventional commercially available raw materials or conventional processing techniques in the art.

[0035] The specific preparation steps of the method for synthesizing homoallylic amines of the present invention are as follows:

[0036] Take a metal catalyst, a ligand, and a primary amine compound with some unprotected amino groups, seal the reaction to obtain an activated complex of metal iridium and the ligand;

[0037] Mix and react a carbonyl catalyst, a primary amine compound with some unprotected amino groups, and an additive, then add an allylation reagent, a base, and the prepared activated complex of metal iridium and the ligand, and continue the reaction;

[0038] After the reaction is completed, separate, dry, and purify to obtain a homoallylic amine product.

[0039] The following examples are helpful for further understanding the present invention, but do not limit the content of the invention.

[0040] (1) Influence of different bases on the reaction

[0041] In this example, the base was screened for the preparation method of (S,E)-6-([1,1'-biphenyl]-4-yl)-1-phenylhex-5-en-3-amine. The general procedure of this example is as follows:

[0042] In a glove box, weigh 1,8-diazabicyclo[5.4.0]undec-7-ene (5.5 mg, 0.030 mmol) into a 10 mL Schlenk tube, add THF (0.20 mL), then add 3-phenylpropylamine (40.5 mg, 0.30 mmol) and zinc bromide (0.101 g, 0.45 mmol, dissolved in 0.3 mL of tetrahydrofuran), and stir at room temperature for 30 minutes; Take another 5 mL vial in the glove box, add [Ir(COD)Cl]2 (4.0 mg, 0.006 mmol), (R,R a )-L1 ligand and 3-phenylpropylamine (20.3 mg, 0.15 mmol) and tetrahydrofuran (0.2 mL), seal and react at 50 °C for 30 minutes to obtain an activated complex of metal iridium and the ligand (which is [Ir(COD)Cl]2, (R,R a) - Complex prepared from L1 ligand and 3 - phenylpropylamine). After 30 minutes, 4 - biphenylyl allyl carbonate (0.3 mmol), 1,8 - diazabicyclo[5.4.0]undec - 7 - ene (DBU) (0.050 g, 0.45 mmol), and freshly prepared activated metal iridium - ligand complex were added to the aforementioned Schlenk tube, and an additional 0.075 mL of tetrahydrofuran and 0.050 mL of deionized water were supplemented. Subsequently, the sealed system was removed from the glove box and placed at room temperature for reaction. After the reaction was completed, an aqueous hydroxylamine solution (0.050 mL, 50 wt.% aqueous solution) was added to the system. After reacting at room temperature for 1 hour, the system was separated with ammonia water (5.0 mL, 25 - 28 wt.% aqueous solution) and dichloromethane (20.0 mL). The aqueous phase was extracted twice more with dichloromethane (20.0 mL×3). After the organic phases were combined, they were dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by column chromatography to obtain the chiral unprotected terminal - substituted homoallylic primary amine compound 3a. The ee value of the product was obtained by HPLC analysis of its derivative reaction with di - tert - butyl dicarbonate.

[0043] The reaction equation is:

[0044]

[0045] The basic parameters of the compound 3a are as follows:

[0046] Pale yellow solid; M.p. 109 - 111 °C; [α] D 25 = +12.6 (c = 0.10, MeOH); 1 H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 7.6 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.48 - 7.40 (m, 4H), 7.38 - 7.28 (m, 3H), 7.26 - 7.17 (m, 3H), 6.51 (d, J = 15.6 Hz, 1H), 6.32 - 6.20 (m, 1H), 3.00 - 2.89 (m, 1H), 2.87 - 2.75 (m, 1H), 2.75 - 2.64 (m, 1H), 2.51 - 2.40 (m, 1H), 2.30 - 2.18 (m, 1H), 1.90 - 1.78 (m, 1H), 1.75 - 1.62 (m, 1H), 1.47 (brs, 2H); 1313C NMR (100 MHz, CDCl3) δ 142.3, 140.9, 140.0, 136.5, 132.3, 128.9, 128.55, 128.51, 127.6, 127.4, 127.0, 126.6, 126.0, 50.8, 42.1, 39.6, 32.8; HRMS (ESI): m / z Calcd. for C 24 H 26 N (M+H) + : 328.2060; Found: 328.2063.

[0047] Table 1 Bases, yields, and ee values of Examples 1 - 11

[0048] Example Serial Number Base Yield (%) ee Value (%) Example 1 DBU 89 91 Example 2 TBD 86 90 Example 3 TMG 87 91 Example 4 <![CDATA[Et3N]]> 88 91 Example 5 DABCO 22 85 Example 6 <![CDATA[Cs2CO3]]> 83 89 Example 7 <![CDATA[NaHCO3]]> 58 71 Example 8 <![CDATA[KO t Bu]]> 71 75 Example 9 <![CDATA[Na2CO3]]> 85 89 Example 10 DIPEA 85 88 Example 11 NaH 30 88

[0049] As can be seen from the examples, good results can be obtained with common inorganic or organic bases, and DBU was selected as the base reagent in subsequent experiments.

[0050] (II) Influence of Different Metal Catalysts and Ligands on the Reaction

[0051] Most of the experimental procedures were the same as in Part (I), except that: the metal catalysts used were adjusted to any one of [Ir(COD)Cl]2, Ir(COD)2BF4, Ir(acac)(COD), [Ir(COD)OMe]2, [Ir(DBCOT)Cl]2, and the ligand was any one of the preferred chiral phosphinimide ligands. The equation for this reaction is as follows:

[0052]

[0053] Table 2 Metal catalysts, ligands, yields, and ee values of Examples 12 - 27

[0054]

[0055]

[0056] As can be seen from the examples, the combination of Ir(COD)2BF4 and L6 gives the best results.

[0057] (III) Influence of Different Solvents on the Reaction

[0058] The experimental procedure was the same as in Part (I), except that: the metal catalyst used was Ir(COD)2BF4, and the ligand was the preferred chiral phosphinimide ligand (R,R a )-L6. The equation for this reaction is as follows:

[0059]

[0060] Table 3 Solvents, yields, and ee values of Examples 28 - 39

[0061] Example Serial Number Solvent Yield (%) ee Value (%) Example 28 <![CDATA[THF / H2O(29:1)]]> 95 97 Example 29 <![CDATA[CH2Cl2 / H2O(29:1)]]> trace - Example 30 <![CDATA[CHCl3 / H2O(29:1)]]> trace - Example 31 <![CDATA[toluene / H2O(29:1)]]> trace - Example 32 <![CDATA[CH3CN / H2O(29:1)]]> n.r. - Example 33 <![CDATA[EtOH / H2O(29:1)]]> trace - Example 34 <![CDATA t BuOMe / H2O(29:1)]]> n.r. - Example 35 <![CDATA[DMF / H2O(29:1)]]> 39 87 Example 36 THF 29 94 Example 37 <![CDATA[THF / H2O(14:1)]]> 45 92 Example 38 <![CDATA[THF / H2O(13:2)]]> 40 92 Example 39 <![CDATA[THF / H2O(4:1)]]> 31 93

[0062] As can be seen from the examples, a mixed system of tetrahydrofuran and water with a ratio of 29:1 has a better reaction effect.

[0063] (IV) Influence of Different Additives on the Reaction

[0064] The experimental procedure was the same as in part (I), except that: the metal catalyst used was Ir(COD)2BF4, the ligand was the preferred chiral phosphinimide ligand (R,R a )-L6, the solvent was the preferred THF and water system, and the equation for this reaction is as follows:

[0065] Table 4 Additives, yields, and ee values of Examples 40 - 48

[0066] Example Serial Number Additive Yield (%) ee Value (%) Example 40 Zinc Chloride 16 88 Example 41 Zinc Bromide 95 97 Example 42 Zinc Iodide 80 96 Example 43 Zinc Acetate 13 70 Example 44 Zinc Phosphate 50 90- Example 45 Zinc Carbonate 20 87- Example 46 Zinc Benzoate 70 55- Example 47 Copper Bromide 39 87 Example 48 Iron Bromide 29 94

[0067] (V) Preparation of Terminal-Substituted Homoallylic Primary Amine Compounds from Different Reaction Raw Materials

[0068] According to the optimal reaction conditions determined from the above experiments, the substrates suitable for the preparation method of chiral unprotected terminal-substituted homoallylic primary amine compounds co-catalyzed by 1,8-diazabicyclo[5.4.0]undec-7-ene skeleton carbonyl catalyst and metal iridium and ligand complex were expanded. The steps of this example are as follows

[0069] Example 49: Synthesis of Compound 3a

[0070]

[0071] In the glove box, 1,8-diazabicyclo[5.4.0]undec-7-ene (5.5 mg, 0.030 mmol) was weighed into a 10 mL Schlenk tube, THF (0.20 mL) was added, and then 3-phenylpropylamine (40.5 mg, 0.30 mmol) and zinc bromide (0.101 g, 0.45 mmol, dissolved in 0.3 mL of tetrahydrofuran) were added, and the mixture was stirred at room temperature for 30 minutes; in another 5 mL vial in the glove box, Ir(COD)2BF4 (5.9 mg, 0.012 mmol), (R,R a) - L6 ligand, 3 - phenylpropylamine (20.3 mg, 0.15 mmol), and tetrahydrofuran (0.2 mL) were sealed and reacted at 50 °C for 30 minutes. After 30 minutes, aryl allyl carbonate (0.3 mmol), 1,8 - diazabicyclo[5.4.0]undec - 7 - ene (DBU) (0.050 g, 0.45 mmol), and freshly prepared activated iridium - ligand complex were added to the aforementioned Schlenk tube, and additional tetrahydrofuran (0.75 mL) and deionized water (0.050 mL) were supplemented. Subsequently, the sealed system was removed from the glove box and reacted at room temperature. After the reaction was completed, aqueous hydroxylamine solution (0.050 mL, 50 wt.% aqueous solution) was added to the system. After reacting at room temperature for 1 hour, the system was separated with ammonia water (5.0 mL, 25 - 28 wt.% aqueous solution) and dichloromethane (20.0 mL), and the aqueous phase was extracted twice with dichloromethane (20.0 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain chiral unprotected terminal - substituted homoallylic primary amine compound 3a (pale yellow oil, 0.0928 g, yield 95%). The ee value of the product was obtained by HPLC analysis of its derivative reacted with di - tert - butyl dicarbonate, and its ee value was 97%.

[0072] Pale yellow solid; M.p. 109 - 111 °C; [α] D 25 = +12.6 (c = 0.10, MeOH); 1 H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 7.6 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.48 - 7.40 (m, 4H), 7.38 - 7.28 (m, 3H), 7.26 - 7.17 (m, 3H), 6.51 (d, J = 15.6 Hz, 1H), 6.32 - 6.20 (m, 1H), 3.00 - 2.89 (m, 1H), 2.87 - 2.75 (m, 1H), 2.75 - 2.64 (m, 1H), 2.51 - 2.40 (m, 1H), 2.30 - 2.18 (m, 1H), 1.90 - 1.78 (m, 1H), 1.75 - 1.62 (m, 1H), 1.47 (brs, 2H); 13 C NMR (100 MHz, CDCl3) δ 142.3, 140.9, 140.0, 136.5, 132.3, 128.9, 128.55, 128.51, 127.6, 127.4, 127.0, 126.6, 126.0, 50.8, 42.1, 39.6, 32.8; HRMS (ESI): m / z Calcd. for C 24 H 26N(M + H) + : 328.2060; Found: 328.2063.

[0073] Example 50: Synthesis of Compound 3b

[0074]

[0075] The addition amounts of each component reagent and the reaction steps are referred to Example 49. Compared with Example 49, the difference is only that 2b is used to replace 2a, and the other conditions are the same as those in Example 49. Compound 3b (yellow oily liquid, 0.0691 g, yield 92%) was obtained by column chromatography.

[0076] The ee value of 3b was obtained by HPLC analysis of its derivative reacted with di-tert-butyl dicarbonate, and its ee value was 94%.

[0077] Yellow oil; [α] D 25 = +12.5 (c = 0.10, MeOH); 1 1H NMR (400 MHz, CDCl3) δ 7.39 - 7.34 (m, 2H), 7.34 - 7.27 (m, 4H), 7.25 - 7.16 (m, 4H), 6.47 (d, J = 15.6 Hz, 1H), 6.27 - 6.15 (m, 1H), 2.97 - 2.87 (m, 1H), 2.85 - 2.74 (m, 1H), 2.73 - 2.63 (m, 1H), 2.48 - 2.37 (m, 1H), 2.27 - 2.15 (m, 1H), 1.89 - 1.76 (m, 1H), 1.73 - 1.60 (m, 1H), 1.31 (brs, 2H); 13 13C NMR (100 MHz, CDCl3) δ 142.2, 137.4, 132.8, 128.6, 128.50, 128.46, 127.3, 127.2, 126.1, 125.9, 50.7, 41.7, 39.3, 32.7; HRMS (ESI): m / z Calcd. For C 18 H 22 N(M + H) + : 252.1747; Found: 252.1749.

[0078] Example 51: Synthesis of Compound 3c

[0079]

[0080] The addition amounts of each component reagent and the reaction steps are shown in Example 49. Compared with Example 49, the difference is only that 2c is used to replace 2a, and the remaining conditions are the same as those in Example 49. Compound 3c (yellow oily liquid, 0.0629 g, yield 79%) was obtained by column chromatography.

[0081] The ee value of 3c was obtained by HPLC analysis of its derivative reacted with di-tert-butyl dicarbonate, and its ee value was 94%.

[0082] Yellow solid; M.p. 43 - 45 °C; [α] D 25 = +15.9 (c = 0.10, MeOH); 1 H NMR (400 MHz, CDCl3) δ 7.33 - 7.24 (m, 4H), 7.24 - 7.16 (m, 3H), 7.12 (d, J = 7.6 Hz, 2H), 6.43 (d, J = 16.0 Hz, 1H), 6.20 - 6.09 (m, 1H), 2.95 - 2.86 (m, 1H), 2.84 - 2.74 (m, 1H), 2.73 - 2.62 (m, 1H), 2.46 - 2.37 (m, 1H), 2.34 (s, 3H), 2.25 - 2.13 (m, 1H), 1.88 - 1.75 (m, 1H), 1.72 - 1.60 (m, 1H), 1.43 (brs, 2H); 13 C NMR (100 MHz, CDCl3) δ 142.3, 137.0, 134.7, 132.6, 129.3, 128.52, 128.50, 126.3, 126.1, 125.9, 50.8, 42.0, 39.5, 32.8, 21.3; HRMS (ESI): m / z Calcd. For C 19 H 24 N (M + H) + : 266.1903; Found: 266.1907.

[0083] Example 52: Synthesis of compound 3d

[0084]

[0085] The addition amounts of each component reagent and the reaction steps are shown in Example 49. Compared with Example 49, the difference is only that 2d is used to replace 2a, and the remaining conditions are the same as those in Example 49. Compound 3d (brown solid, 0.0692 g, yield 75%) was obtained by column chromatography.

[0086] The ee value of 3d was obtained by HPLC analysis of its derivative reacted with di-tert-butyl dicarbonate, and its ee value was 93%.

[0087] Brown solid; M.p. 34 - 35 °C; [α] D 25 = +13.0 (c = 0.10, MeOH); 1 H NMR (400 MHz, CDCl3) δ 7.36 - 7.27 (m, 6H), 7.24 - 7.16 (m, 3H), 6.45 (d, J = 15.6 Hz, 1H), 6.21 - 6.11 (m, 1H), 2.95 - 2.86 (m, 1H), 2.84 - 2.74 (m, 1H), 2.73 - 2.62 (m, 1H), 2.47 - 2.37 (m, 1H), 2.25 - 2.14 (m, 1H), 1.87 - 1.76 (m, 1H), 1.72 - 1.60 (m, 1H), 1.52 (brs, 2H), 1.32 (s, 9H); 13 C NMR (100 MHz, CDCl3) δ 150.4, 142.3, 134.7, 132.6, 128.53, 128.51, 126.5, 125.93, 125.89, 125.6, 50.8, 42.0, 39.5, 34.7, 32.8, 31.4; HRMS (ESI): m / z Calcd. For C 22 H 30 N (M + H) + : 308.2373; Found: 308.2374.

[0088] Example 53: Synthesis of Compound 3e

[0089]

[0090] The addition amounts of each component reagent and the reaction steps are shown in Example 49. Compared with Example 49, the difference is only that 2e is used to replace 2a, and the other conditions are the same as those in Example 49. Compound 3e (brown solid, 0.0690 g, yield 82%) was obtained by column chromatography.

[0091] The ee value of 3e was obtained by HPLC analysis of its derivative reacted with di - tert - butyl dicarbonate, and its ee value was 94%.

[0092] Brown solid; M.p. 53 - 54 °C; [α] D 25 = +16.3 (c = 0.10, MeOH); 11H NMR (400 MHz, CDCl3) δ 7.34 - 7.27 (m, 4H), 7.25 - 7.16 (m, 3H), 6.86 (d, J = 8.0 Hz, 2H), 6.41 (d, J = 16.0 Hz, 1H), 6.12 - 6.00 (m, 1H), 3.81 (s, 3H), 2.95 - 2.85 (m, 1H), 2.84 - 2.74 (m, 1H), 2.73 - 2.62 (m, 1H), 2.46 - 2.35 (m, 1H), 2.25 - 2.13 (m, 1H), 1.88 - 1.76 (m, 1H), 1.73 - 1.60 (m, 1H), 1.48 (brs, 2H); 13 13C NMR (100 MHz, CDCl3) δ 159.0, 142.3, 132.1, 130.3, 128.48, 128.47, 127.3, 125.9, 125.0, 114.0, 55.4, 50.8, 41.9, 39.5, 32.8; HRMS (ESI): m / z Calcd. For C 19 H 24 NO (M + H) + : 282.1852; Found: 282.1855.

[0093] Example 54: Synthesis of Compound 3f

[0094]

[0095] The addition amounts of each component reagent and the reaction steps are referred to Example 49. Compared with Example 49, the only difference is that 2f is used to replace 2a, and the other conditions are the same as those in Example 49. Compound 3f (yellow solid, 0.0667 g, yield 83%) was obtained by column chromatography.

[0096] The ee value of 3f was obtained by HPLC analysis of its derivative reacted with di-tert-butyl dicarbonate, and its ee value was 95%.

[0097] Yellow solid; M.p. 42 - 43 °C; [α] D 25 = +9.8 (c = 0.10, MeOH); 11H NMR (400 MHz, CDCl3) δ 7.35 - 7.27 (m, 4H), 7.24 - 7.16 (m, 3H), 6.99 (t, J = 8.4 Hz, 2H), 6.42 (d, J = 15.6 Hz, 1H), 6.16 - 6.06 (m, 1H), 2.96 - 2.86 (m, 1H), 2.84 - 2.74 (m, 1H), 2.72 - 2.62 (m, 1H), 2.47 - 2.35 (m, 1H), 2.25 - 2.13 (m, 1H), 1.88 - 1.75 (m, 1H), 1.73 - 1.60 (m, 1H), 1.53 (brs, 2H); 13 13C NMR (100 MHz, CDCl3) δ 162.2 (d, J C-F = 245 Hz), 142.2, 133.6 (d, J C-F = 3.3 Hz), 131.6, 128.55, 128.49, 127.6 (d, J C-F = 7.6 Hz), 127.1 (d, J C-F = 2.2 Hz), 126.0, 115.5 (d, J C-F = 21.7 Hz), 50.7, 41.9, 39.5, 32.8; 19 19F NMR (376 MHz, CDCl3) δ -115.2; HRMS (ESI): m / z Calcd. For C 18 H 21 FN (M + H) + : 270.1653; Found: 270.1657.

[0098] Example 55: Synthesis of Compound 3g

[0099]

[0100] The addition amounts of each component reagent and the reaction steps are referred to Example 49. Compared with Example 49, the difference is only that 2 g is used to replace 2a, and the other conditions are the same as those in Example 49. Compound 3g (yellow solid, 0.0688 g, yield 80%) was obtained by column chromatography.

[0101] The ee value of 3g was obtained by HPLC analysis of its derivative reacted with di-tert-butyl dicarbonate, and its ee value was 94%.

[0102] Yellow solid; M.p. 45 - 46 °C; [α] D 25 = +12.9 (c = 0.10, MeOH); 11H NMR (400 MHz, CDCl3) δ 7.32 - 7.23 (m, 6H), 7.22 - 7.16 (m, 3H), 6.40 (d, J = 16.0 Hz, 1H), 6.23 - 6.12 (m, 1H), 2.96 - 2.85 (m, 1H), 2.84 - 2.73 (m, 1H), 2.72 - 2.61 (m, 1H), 2.46 - 2.36 (m, 1H), 2.26 - 2.13 (m, 1H), 1.87 - 1.74 (m, 1H), 1.72 - 1.60 (m, 1H), 1.44 (brs, 2H); 13 13C NMR (100 MHz, CDCl3) δ 142.2, 136.0, 132.8, 131.5, 128.8, 128.55, 128.49, 128.1, 127.4, 126.0, 50.7, 41.9, 39.6, 32.8; HRMS (ESI): m / z Calcd. For C 18 H 21 ClN (M + H) + : 286.1357; Found: 286.1360.

[0103] Example 56: Synthesis of Compound 3h

[0104]

[0105] The addition amounts of each component reagent and the reaction steps are referred to Example 49. Compared with Example 49, the difference is only that 2h is used to replace 2a, and the other conditions are the same as those in Example 49. Compound 3h (yellow solid, 0.0764 g, yield 77%) was obtained by column chromatography.

[0106] The ee value of 3h was obtained by HPLC analysis of its derivative reacted with di - tert - butyl dicarbonate, and its ee value was 96%.

[0107] Yellow solid; M.p. 49 - 51 °C; [α] D 25 = +9.3 (c = 0.10, MeOH); 11H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 7.6 Hz, 2H), 7.30 (t, J = 7.2 Hz, 2H), 7.24 - 7.14 (m, 5H), 6.39 (d, J = 15.6 Hz, 1H), 6.26 - 6.15 (m, 1H), 2.97 - 2.87 (m, 1H), 2.85 - 2.73 (m, 1H), 2.72 - 2.61 (m, 1H), 2.46 - 2.36 (m, 1H), 2.26 - 2.13 (m, 1H), 1.88 - 1.75 (m, 1H), 1.73 - 1.60 (m, 1H), 1.33 (brs, 2H); 13 13C NMR (100 MHz, CDCl3) δ 142.2, 136.4, 131.7, 131.5, 128.53, 128.47, 128.3, 127.7, 126.0, 120.9, 50.7, 42.0, 39.6, 32.8; HRMS (ESI): m / z Calcd. For C 18 H 21 BrN (M + H) + : 330.0852; Found: 330.0855.

[0108] Example 57: Synthesis of Compound 3i

[0109]

[0110] The addition amounts of each component reagent and the reaction steps are referred to Example 49. Compared with Example 49, the difference is only that 2i is used to replace 2a, and the other conditions are the same as those in Example 49. Compound 3i (pale yellow solid, 0.0854 g, yield 92%) was obtained by column chromatography.

[0111] The ee value of 3i was obtained by HPLC analysis of its derivative reacted with di-tert-butyl dicarbonate, and its ee value was 96%.

[0112] Pale yellow solid; M.p. 52 - 54 °C; [α] D 25 = +9.5 (c = 0.10, MeOH); 1 1H NMR (400 MHz, CDCl3)

[0113] δ8.07 - 7.99 (m, 2H), 7.48 - 7.40 (m, 2H), 7.32 - 7.16 (m, 5H), 6.29 (d, J=15.6 Hz, 1H), 6.01 - 5.98 (m, 1H), 3.85 (s, 3H), 2.65 - 2.45 (m, 3H), 2.35 - 2.23 (m, 1H), 2.10 - 1.87 (m, 2H), 1.77 - 1.63 (m, 3H); 13 C NMR(100 MHz, CDCl3) δ166.7, 142.6, 142.0, 129.6, 129.3, 129.3, 128.4, 128.3, 126.8, 126.2, 52.1, 51.9, 39.3, 33.2, 32.6; HRMS(ESI): m / z Calcd. For C 20 H 24 NO2(M + H) + : 310.1082; Found: 310.1079.

[0114] Example 58: Synthesis of Compound 3j

[0115]

[0116] The addition amounts of each component reagent and the reaction steps are referred to Example 49. Compared with Example 49, the difference is only that 2j is used to replace 2a, and the other conditions are the same as those in Example 49. Compound 3j (brown solid, 0.0569 g, yield 59%) was obtained by column chromatography.

[0117] The ee value of 3j was obtained by HPLC analysis of its derivative reacted with di - tert - butyl dicarbonate, and its ee value was 95%.

[0118] Brown solid; M.p. 63 - 64 °C; [α] D 25 = + 9.3 (c = 0.10, MeOH); 1 H NMR(400 MHz, CDCl3) δ

[0119] 7.55 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.32 - 7.27 (m, 2H), 7.24 - 7.16 (m, 3H), 6.49 (d, J = 16.0 Hz, 1H), 6.37 - 6.27 (m, 1H), 2.99 - 2.89 (m, 1H), 2.85 - 2.74 (m, 1H), 2.73 - 2.62 (m, 1H), 2.49 - 2.40 (m, 1H), 2.30 - 2.19 (m, 1H), 1.88 - 1.77 (m, 1H), 1.73 - 1.62 (m, 1H), 1.44 (brs, 2H); 13 13C NMR (100 MHz, CDCl3) δ 142.1, 140.9 (q, J = 1.4 Hz), 131.5, 130.4, 129.1 (q, J = 32.1 Hz), 128.6, 128.5, 126.3, 126.0, 125.6 (q, J = 3.8 Hz), 124.4 (q, J = 270.2 Hz), 50.7, 41.9, 39.6, 32.8; 19 19F NMR (376 MHz, CDCl3) δ -62.4; HRMS (ESI): m / z Calcd. For C 19 H 21 F3N (M + H) + : 320.1621; Found: 320.1624.

[0120] Example 59: Synthesis of Compound 3k

[0121]

[0122] The addition amounts of each component reagent and the reaction steps are referred to Example 49. Compared with Example 49, the difference is only that 2k is used to replace 2a, and the other conditions are the same as those in Example 49. Compound 3k (yellow oil, 0.0711 g, yield 89%) was obtained by column chromatography.

[0123] The ee value of 3k was obtained by HPLC analysis of its derivative reacted with di-tert-butyl dicarbonate, and its ee value was 94%.

[0124] Yellow oil; [α] D 25 = +14.0 (c = 0.20, MeOH); 1 1H NMR (400 MHz, CDCl3) δ 7.30 (t, J = 7.6 Hz,

[0125] 2H), 7.24 - 7.13 (m, 6H), 7.04 (d, J = 7.6 Hz, 1H), 6.44 (d, J = 16.0 Hz, 1H), 6.25 - 6.13 (m, 1H), 2.96 - 2.87 (m, 1H), 2.85 - 2.74 (m, 1H), 2.73 - 2.62 (m, 1H), 2.47 - 2.38 (m, 1H), 2.35 (s, 3H), 2.25 - 2.15 (m, 1H), 1.88 - 1.76 (m, 1H), 1.74 - 1.60 (m, 3H); 13 C NMR (100 MHz, CDCl3) δ 142.3, 138.2, 137.4, 132.9, 128.6, 128.53, 128.50, 128.1, 127.1, 126.9, 125.9, 123.3, 50.7, 41.9, 39.5, 32.8, 21.5; HRMS (ESI): m / z Calcd. For C 19 H 24 N (M + H) + : 266.1903; Found: 266.1908.

[0126] Example 60: Synthesis of Compound 3l

[0127]

[0128] The addition amounts of each component reagent and the reaction steps are shown in Example 49. Compared with Example 49, the only difference is that 2l is used to replace 2a, and the other conditions are the same as those in Example 49. Compound 3l (yellow oil, 0.0464 g, yield 48%) was obtained by column chromatography.

[0129] The ee value of 3l was obtained by HPLC analysis of its derivative reacted with di - tert - butyl dicarbonate, and its ee value was 95%.

[0130] Yellow oil; [α] D 25 = +13.4 (c = 0.10, MeOH); 1 H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 7.50

[0131] (d, J = 7.6 Hz, 1H), 7.46 (d, J = 7.2 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.29 (t, J = 7.2 Hz, 2H), 7.24 - 7.16 (m, 3H), 6.48 (d, J = 15.6 Hz, 1H), 6.34 - 6.23 (m, 1H), 2.99 - 2.89 (m, 1H), 2.85 - 2.74 (m, 1H), 2.73 - 2.62 (m, 1H), 2.50 - 2.39 (m, 1H), 2.29 - 2.17 (m, 1H), 1.89 - 1.76 (m, 1H), 1.74 - 1.65 (m, 1H), 1.62 (brs, 2H); 13 13C NMR (100 MHz, CDCl3) δ 142.1, 138.2, 131.5, 131.0 (q, J = 31.8 Hz), 129.5, 129.4, 129.1, 128.6, 128.5, 126.0, 124.3 (q, J = 270.8 Hz), 123.8 (q, J = 3.6 Hz), 122.8 (q, J = 3.6 Hz), 50.6, 41.9, 39.5, 32.8; 19 19F NMR (376 MHz, CDCl3) δ -62.7; HRMS (ESI): m / z Calcd. For C 19 H 21 F3N (M + H) + : 320.1621; Found: 320.1622.

[0132] Example 61: Synthesis of Compound 3m

[0133]

[0134] The addition amounts of each component reagent and the reaction steps are shown in Example 49. Compared with Example 49, the difference is only that 2m is used to replace 2a, and the other conditions are the same as those in Example 49. Compound 3m (yellow oil, 0.0480 g, yield 54%) was obtained by column chromatography.

[0135] The ee value of 3m was obtained by HPLC analysis of its derivative reacted with di-tert-butyl dicarbonate, and its ee value was 94%.

[0136] Yellow oil; [α] D 25 = +9.3 (c = 0.10, MeOH); 1 1H NMR (400 MHz, CDCl3) δ 8.20 (t, J = 2.0 Hz,

[0137] 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.0 Hz, 1H), 8.05 (dd, J = 8.0, 1.2 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 7.29 (t, J = 7.6 Hz, 2H), 7.23 - 7.15 (m, 3H), 6.50 (d, J = 15.6 Hz, 1H), 6.42 - 6.32 (m, 1H), 3.00 - 2.90 (m, 1H), 2.85 - 2.74 (m, 1H), 2.73 - 2.62 (m, 1H), 2.51 - 2.40 (m, 1H), 2.30 - 2.20 (m, 1H), 1.89 - 1.77 (m, 1H), 1.74 - 1.62 (m, 1H), 1.39 (brs, 2H); 13 13C NMR (100 MHz, CDCl3) δ 148.7, 142.0, 139.2, 132.1, 131.0, 130.5, 129.5, 128.6, 128.5, 126.0, 121.8, 120.7, 50.6, 41.9, 39.6, 32.7; HRMS (ESI): m / z Calcd. For C 18 H 21 N2O2 (M + H) + : 297.1598; Found: 297.1602.

[0138] Example 62: Synthesis of Compound 3n

[0139]

[0140] The addition amounts of each component reagent and the reaction steps are referred to Example 49. Compared with Example 49, the difference is only that 2n is used to replace 2a, and the other conditions are the same as those in Example 49. Compound 3n (yellow solid, 0.0677 g, yield 71%) was obtained by column chromatography.

[0141] The ee value of 3n was obtained by HPLC analysis of its derivative reacted with di-tert-butyl dicarbonate, and its ee value was 96%.

[0142] Yellow solid; M.p. 57 - 58 °C; [α] D 25 = +9.0 (c = 0.10, MeOH); 1 1H NMR (400 MHz, CDCl3) δ

[0143] 7.42 (d, J = 2.0 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.32 - 7.27 (m, 2H), 7.24 - 7.17 (m, 3H), 7.15 (dd, J = 8.4, 2.0 Hz, 1H), 6.35 (d, J = 16.0 Hz, 1H), 6.27 - 6.15 (m, 1H), 2.96 - 2.87 (m, 1H), 2.84 - 2.73 (m, 1H), 2.73 - 2.62 (m, 1H), 2.47 - 2.36 (m, 1H), 2.26 - 2.15 (m, 1H), 1.87 - 1.75 (m, 1H), 1.72 - 1.59 (m, 1H), 1.33 (brs, 2H); 13 C NMR (100 MHz, CDCl3) δ 142.1, 137.6, 132.7, 130.8, 130.5, 130.4, 129.7, 128.6, 128.5, 127.8, 126.0, 125.4, 50.6, 41.9, 39.6, 32.8; HRMS (ESI): m / z Calcd. For C 18 H 20 Cl2N (M + H) + : 320.0967; Found: 320.0969.

[0144] Example 63: Synthesis of Compound 3o

[0145]

[0146] The addition amounts of each component reagent and the reaction steps are referred to Example 49. Compared with Example 49, the difference is only that 2o is used to replace 2a, and the other conditions are the same as those in Example 49. Compound 3o (white solid, 0.0753 g, yield 83%) was obtained by column chromatography.

[0147] The ee value of 3o was obtained by HPLC analysis of its derivative reacted with di-tert-butyl dicarbonate, and its ee value was 96%.

[0148] Yellow solid; M.p. 75 - 77 °C; [α] D 25 = +19.9 (c = 0.10, MeOH); 1 H NMR (400 MHz, CDCl3) δ

[0149] 7.84 - 7.74 (m, 3H), 7.70 (s, 1H), 7.59 (dd, J = 8.4, 1.6 Hz, 1H), 7.50 - 7.39 (m, 2H), 7.31 (t, J = 7.2 Hz, 2H), 7.25 - 7.18 (m, 3H), 6.63 (d, J = 16.0 Hz, 1H), 6.41 - 6.28 (m, 1H), 3.02 - 2.91 (m, 1H), 2.88 - 2.76 (m, 1H), 2.76 - 2.65 (m, 1H), 2.54 - 2.43 (m, 1H), 2.34 - 2.21 (m, 1H), 1.93 - 1.79 (m, 1H), 1.77 - 1.63 (m, 1H), 1.37 (brs, 2H); 13 C NMR (100 MHz, CDCl3) δ 142.3, 134.9, 133.8, 132.9, 128.55, 128.52, 128.2, 128.0, 127.9, 127.8, 126.3, 126.0, 125.79, 125.77, 123.6, 50.8, 42.1, 39.6, 32.8; HRMS (ESI): m / z Calcd. For C 22 H 24 N (M + H) + : 302.1903; Found: 302.1906.

[0150] Example 64: Synthesis of Compound 3p

[0151]

[0152] The addition amounts of each component reagent and the reaction steps are referred to Example 49. Compared with Example 49, the difference is only that 2p is used to replace 2a, and the other conditions are the same as those in Example 49. Compound 3p (orange oil, 0.0626 g, yield 87%) was obtained by column chromatography.

[0153] The ee value of 3p was obtained by HPLC analysis of its derivative reacted with di - tert - butyl dicarbonate, and its ee value was 94%.

[0154] Orange oil; [α] D 25 = +14.1 (c = 0.10, MeOH); 1 H NMR (400 MHz, CDCl3) δ 7.34 - 7.23 (m, 3H),

[0155] 7.23 - 7.15 (m, 3H), 6.38 - 6.32 (m, 1H), 6.27 (d, J = 15.6 Hz, 1H), 6.18 - 6.04 (m, 2H), 2.94 - 2.84 (m, 1H), 2.83 - 2.72 (m, 1H), 2.71 - 2.60 (m, 1H), 2.44 - 2.34 (m, 1H), 2.22 - 2.10 (m, 1H), 1.87 - 1.73 (m, 1H), 1.71 - 1.58 (m, 1H), 1.52 (brs, 2H); 13 C NMR(100 MHz, CDCl3) δ 152.9, 142.2, 141.6, 128.51, 128.49, 126.2, 125.9, 121.3, 111.3, 106.8, 50.7, 41.7, 39.5, 32.8; HRMS(ESI): m / z Calcd. For C 16 H 20 NO(M + H) + : 242.1539; Found: 242.1540.

[0156] Example 65: Synthesis of Compound 3q

[0157]

[0158] The addition amounts of each component reagent and the reaction steps are referred to Example 49. Compared with Example 49, the difference is only that 2q is used to replace 2a, and the other conditions are the same as those in Example 49. Compound 3q (yellow oil, 0.0591 g, yield 77%) was obtained by column chromatography.

[0159] The ee value of 3q was obtained by HPLC analysis of its derivative reacted with di - tert - butyl dicarbonate, and its ee value was 94%.

[0160] Yellow oil; [α] D 25 = +18.3 (c = 0.11, MeOH); 1 H NMR(400 MHz, CDCl3) δ 7.29 (t, J = 7.2 Hz,

[0161] 2H), 7.24 - 7.16 (m, 3H), 7.11 (d, J = 4.8 Hz, 1H), 6.97 - 6.92 (m, 1H), 6.91 - 6.87 (m, 1H), 6.59 (d, J = 15.6 Hz, 1H), 6.08 - 5.98 (m, 1H), 2.95 - 2.85 (m, 1H), 2.84 - 2.73 (m, 1H), 2.72 - 2.61 (m, 1H), 2.44 - 2.34 (m, 1H), 2.22 - 2.10 (m, 1H), 1.88 - 1.74 (m, 1H), 1.72 - 1.59 (m, 1H), 1.44 (brs, 2H); 13 C NMR (100 MHz, CDCl3) δ 142.7, 142.2, 128.54, 128.50, 127.4, 127.3, 126.0, 125.9, 124.9, 123.6, 50.7, 41.8, 39.5, 32.8; HRMS (ESI): m / z Calcd. For C 16 H 20 NS (M + H) + : 258.1311; Found: 258.1314.

[0162] Example 66: Synthesis of Compound 3r

[0163]

[0164] The addition amounts of each component reagent and the reaction steps are referred to Example 49. Compared with Example 49, the difference is only that 2r is used to replace 2a, and the other conditions are the same as those in Example 49. Compound 3r (pale yellow solid, 0.0507 g, yield 67%) was obtained by column chromatography.

[0165] The ee value of 3r was obtained by HPLC analysis of its derivative reacted with di - tert - butyl dicarbonate, and its ee value was 94%.

[0166] Pale yellow oil; [α] D 25 = +20.1 (c = 0.10, MeOH); 1 H NMR (400 MHz, CDCl3) δ 8.51 (t, J = 1.8

[0167] Hz, 1H), 8.33 (ddd, J = 3.6, 2.2, 1.4 Hz, 1H), 7.55 - 7.51 (m, 2H), 7.32 - 7.16 (m, 4H), 7.02 (dd, J = 7.8, 3.8 Hz, 1H), 6.41 - 6.31 (m, 1H), 6.04 - 5.92 (m, 1H), 2.65 - 2.45 (m, 3H), 2.33 - 2.27 (m, 1H), 2.10 - 1.87 (m, 4H), 1.77 - 1.63 (m, 1H); 13 C NMR (100 MHz, CDCl3) δ 148.6, 148.0, 142.6, 133.2, 132.8, 130.8, 128.4, 128.3, 127.0, 126.2, 123.6, 51.9, 39.3, 33.2, 32.6; HRMS (ESI): m / z Calcd. For C 17 H 21 N2 (M + H) + : 253.1699; Found: 253.1697.

[0168] Example 67: Synthesis of Compound 3s

[0169]

[0170] The addition amounts of each component reagent and the reaction steps are referred to Example 49. Compared with Example 49, the difference is only that 2s is used to replace 2a, the dosage of DFO is increased to 20 mol%, and the ligand (S,S a )-L6 is used, and the other conditions are the same as those in Example 49. Compound 3s (pale yellow oil, 0.0351 g, yield 54%) was obtained by column chromatography.

[0171] The ee value of 3s was obtained by HPLC analysis of the derivative of its reaction with benzoyl chloride, and its ee value was 89%.

[0172] Pale yellow oil; [α] D 25 = -11.4 (c = 0.10, MeOH); 1 H NMR (400 MHz, CDCl3) δ 7.28 (t, J = 8.0

[0173] Hz, 2H), 7.22 - 7.15 (m, 3H), 6.12 - 5.98 (m, 2H), 5.67 - 5.57 (m, 1H), 5.57 - 5.46 (m, 1H), 2.84 - 2.70 (m, 2H), 2.69 - 2.58 (m, 1H), 2.31 - 2.21 (m, 1H), 2.09 - 1.97 (m, 1H), 1.81 - 1.70 (m, 4H), 1.66 - 1.55 (m, 1H), 1.42 (brs, 2H); 13 C NMR (100 MHz, CDCl₃) δ 142.4, 133.4, 131.5, 128.5, 128.1, 128.0, 125.9, 50.8, 41.5, 39.5, 32.8, 18.2; HRMS (ESI): m / z Calcd. For C 15 H 22 N (M + H) + : 216.1747; Found: 216.1751.

[0174] Example 68: Synthesis of Compound 3t

[0175]

[0176] The addition amounts of each component reagent and the reaction steps are referred to Example 49. Compared with Example 49, the difference is only that 2t is used to replace 2a, the dosage of DFO is increased to 20 mol%, and the ligand (S,S a )-L6 is used, and the other conditions are the same as those in Example 49. Compound 3t (brown oil, 0.0589 g, yield 72%) was obtained by column chromatography.

[0177] The ee value of 3t was obtained by HPLC analysis of its derivative reacted with benzoyl chloride, and its ee value was 90%.

[0178] Brown oil; [α] D 25 = -11.3 (c = 0.10, MeOH); 1 H NMR (400 MHz, CDCl₃) δ 7.28 (t, J = 8.0 Hz,

[0179] 2H), 7.23 - 7.15 (m, 3H), 6.13 - 5.95 (m, 2H), 5.66 - 5.56 (m, 1H), 5.56 - 5.47 (m, 1H), 2.86 - 2.78 (m, 1H), 2.78 - 2.71 (m, 1H), 2.69 - 2.58 (m, 1H), 2.31 - 2.22 (m, 1H), 2.10 - 1.99 (m, 3H), 1.81 - 1.70 (m, 1H), 1.66 - 1.57 (m, 1H), 1.54 (brs, 2H), 1.42 - 1.22 (m, 6H), 0.88 (t, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 142.3, 133.7, 133.5, 130.0, 128.5, 128.2, 125.9, 50.8, 41.5, 39.4, 32.8, 32.7, 31.5, 29.1, 22.6, 14.2; HRMS (ESI): m / z Calcd. For C 19 H 30 N (M + H) + : 272.2373; Found: 272.2378.

[0180] Example 69: Synthesis of Compound 3u

[0181]

[0182] The addition amounts of each component reagent and the reaction steps are referred to Example 49. Compared with Example 49, the difference is only that 2u is used to replace 2a, the dosage of DFO is increased to 20 mol%, and the ligand (S,S a ) - L6 is used, and the remaining conditions are the same as those in Example 49. Compound 3u (orange oil, 0.0562 g, yield 82%) was obtained by column chromatography.

[0183] The ee value of 3u was obtained by HPLC analysis of its derivative reacted with benzoyl chloride, and its ee value was 80%.

[0184] Orange oil; [α] D 25 = -11.3 (c = 0.10, MeOH); 1 H NMR (400 MHz, CDCl3) δ 7.28 (t, J = 7.6 Hz,

[0185] 2H), 7.22 - 7.15 (m, 3H), 6.30 (dd, J = 14.8, 10.8 Hz, 1H), 5.81 (d, J = 10.8 Hz, 1H), 5.56 - 5.46 (m, 1H), 2.85 - 2.79 (m, 1H), 2.79 - 2.71 (m, 1H), 2.69 - 2.59 (m, 1H), 2.35 - 2.26 (m, 1H), 2.12 - 2.02 (m, 1H), 1.82 - 1.71 (m, 7H), 1.67 - 1.56 (m, 1H), 1.30 (brs, 2H); 13 C NMR (100 MHz, CDCl3) δ 142.4, 133.9, 129.7, 128.5, 128.0, 125.9, 125.0, 50.9, 41.9, 39.6, 32.8, 26.0, 18.4; HRMS (ESI): m / z Calcd. For C 16 H 24 N (M + H) + : 230.1903; Found: 230.1901.

[0186] Example 70: Synthesis of Compound 3v

[0187]

[0188] The addition amounts of each component reagent and the reaction steps are referred to Example 49. Compared with Example 49, the only difference is that 1b is used to replace 1a, 2s is used to replace 2a, the dosage of DFO is increased to 20 mol%, and the ligand (S,S a )-L6 is used, and the remaining conditions are the same as those in Example 49. Compound 3v (brown solid, 0.0910 g, yield 79%) was obtained by column chromatography.

[0189] The ee value of 3v was obtained by HPLC analysis of its derivative reacted with benzoyl chloride, and its ee value was 91%.

[0190] Brown oil; [α] D 25 = -5.1 (c = 0.10, MeOH); 1 H NMR (400 MHz, CDCl3) δ 6.11 - 5.94 (m, 2H),

[0191] 5.66 - 5.46 (m, 2H), 2.82 - 2.71 (m, 1H), 2.27 - 2.17 (m, 1H), 2.04 (q, J = 7.2 Hz, 2H), 2.01 - 1.91 (m, 1H), 1.45 - 1.20 (m, 12H), 0.91 (t, J = 6.8 Hz, 3H), 0.87 (t, J = 6.8 Hz, 3H); 13 CNMR (100 MHz, CDCl3) δ 133.5, 133.2, 130.2, 128.8, 51.0, 41.5, 40.0, 32.7, 31.6, 29.2, 22.7, 19.5, 14.3, 14.2; HRMS (ESI): m / z Calcd. For C 14 H 28 N (M + H) + : 210.2216; Found: 210.2220.

[0192] Example 71: Synthesis of Compound 3w

[0193]

[0194] The addition amounts of each component reagent and the reaction steps are referred to Example 49. Compared with Example 49, the difference is only that 1c is used to replace 1a and 2e is used to replace 2a, and the other conditions are the same as those in Example 49. Compound 3w (brown solid, 0.0910 g, yield 79%) was obtained by column chromatography.

[0195] The ee value of 3w was obtained by HPLC analysis of its derivative reacted with di - tert - butyl dicarbonate, and its ee value was 91%.

[0196] Brown oil; M.p. 35 - 36 °C; [α] D 25 = +23.4 (c = 0.10, MeOH); 1 H NMR (400 MHz, CDCl3) δ 7.28

[0197] (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 6.38 (d, J = 15.6 Hz, 1H), 6.11 - 5.98 (m, 1H), 3.79 (s, 3H), 3.08 - 2.97 (m, 1H), 2.33 - 2.22 (m, 1H), 2.20 - 2.08 (m, 1H), 1.50 (brs, 2H), 1.11 (d, J = 6.0 Hz, 3H); 1313C NMR (100 MHz, CDCl3) δ 158.9, 131.9, 130.4, 127.2, 125.5, 114.0, 55.4, 47.0, 43.9, 23.7; HRMS (ESI): m / z Calcd. For C 12 H 18 NO (M + H) + : 192.1383; Found: 192.1379.

[0198] Example 72: Synthesis of Compound 3x

[0199]

[0200] The addition amounts of each component reagent and the reaction steps are shown in Example 49. Compared with Example 49, the difference is only that 1c is used to replace 1a and 2e is used to replace 2a, and the remaining conditions are the same as those in Example 49. Compound 3x (yellow solid, 0.0709 g, yield 96%) was obtained by column chromatography.

[0201] The ee value of 3x was obtained by HPLC analysis of its derivative reacted with di-tert-butyl dicarbonate, and its ee value was 96%.

[0202] Yellow solid; M.p. 69 - 70 °C; [α] D 25 = +22.8 (c = 0.10, MeOH); 1 1H NMR (400 MHz, CDCl3) δ

[0203] 7.60 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 7.6 Hz, 2H), 7.48 - 7.40 (m, 4H), 7.34 (t, J = 7.2 Hz, 1H), 6.50 (d, J = 15.6 Hz, 1H), 6.32 - 6.22 (m, 1H), 3.02 - 2.92 (m, 1H), 2.44 - 2.34 (m, 1H), 2.22 - 2.10 (m, 1H), 1.84 - 1.69 (m, 1H), 1.37 (brs, 2H), 1.29 (t, J = 6.4 Hz, 2H), 0.93 (t, J = 7.6 Hz, 6H); 13 13C NMR (100 MHz, CDCl3) δ 140.9, 140.0, 136.6, 132.1, 128.9, 127.9, 127.4, 127.0, 126.6, 48.9, 47.3, 42.5, 25.0, 23.6, 22.2; HRMS (ESI): m / z Calcd. For C 20 H 26 N (M + H)+ : 280.2060; Found: 280.2062.

[0204] Example 73: Synthesis of Compound 3y

[0205]

[0206] The addition amounts of each component reagent and the reaction steps are referred to Example 49. Compared with Example 49, the difference is only that 1d is used to replace 1a, and the other conditions are the same as those in Example 49. Compound 3y (yellow solid, 0.0549 g, yield 60%) was obtained by column chromatography.

[0207] The ee value of 3y was obtained by HPLC analysis of its derivative reacted with di-tert-butyl dicarbonate, and its ee value was 97%.

[0208] Yellow solid; M.p. 102 - 104 °C; [α] D 25 = +26.0 (c = 0.10, MeOH); 1 H NMR (400 MHz, CDCl3)

[0209] δ 7.60 (d, J = 7.6 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.48 - 7.40 (m, 4H), 7.34 (t, J = 7.2 Hz, 1H), 6.50 (d, J = 16.0 Hz, 1H), 6.34 - 6.20 (m, 1H), 2.76 - 2.60 (m, 1H), 2.52 - 2.40 (m, 1H), 2.22 - 2.10 (m, 1H), 1.88 - 1.63 (m, 5H), 1.40 - 0.98 (m, 8H); 13 C NMR (100 MHz, CDCl3) δ 140.9, 139.9, 136.7, 131.9, 128.9, 128.7, 127.3, 127.0, 126.6, 55.9, 43.6, 38.8, 29.9, 28.4, 26.8, 26.6, 26.5; HRMS (ESI): m / z Calcd. For C 22 H 28 N (M + H) + : 306.2216; Found: 306.2220.

[0210] Example 74: Synthesis of Compound 3z

[0211]

[0212] The addition amounts of each component reagent and the reaction steps are shown in Example 49. Compared with Example 49, the difference is only that 1e is used to replace 1a, and the other conditions are the same as those in Example 49. Compound 3z (pale yellow solid, 0.0926 g, yield 86%) was obtained by column chromatography.

[0213] The ee value of 3z was obtained by HPLC analysis of its derivative reacted with di-tert-butyl dicarbonate, and its ee value was 97%.

[0214] Pale yellow solid; M.p. 119 - 121 °C; [α] D 25 = +3.4 (c = 0.10, MeOH); 1 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H), 7.47 - 7.39 (m, 4H), 7.34 (t, J = 7.2 Hz, 1H), 7.13 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 6.50 (d, J = 16.0 Hz, 1H), 6.32 - 6.18 (m, 1H), 3.79 (s, 3H), 2.97 - 2.87 (m, 1H), 2.79 - 2.69 (m, 1H), 2.68 - 2.58 (m, 1H), 2.49 - 2.39 (m, 1H), 2.28 - 2.17 (m, 1H), 1.86 - 1.74 (m, 1H), 1.70 - 1.58 (m, 1H), 1.46 (brs, 2H); 13 13C NMR (100 MHz, CDCl3) δ 157.9, 140.9, 140.0, 136.5, 134.3, 132.3, 129.4, 128.9, 127.6, 127.4, 127.0, 126.6, 113.9, 55.4, 50.7, 42.1, 39.8, 31.9; HRMS (ESI): m / z Calcd. For C 25 H 28 NO (M + H) + : 358.2165; Found: 358.2169.

[0215] Example 75: Synthesis of compound 3aa

[0216]

[0217] The addition amounts of each component reagent and the reaction steps are shown in Example 49. Compared with Example 49, the difference is only that 1f is used to replace 1a, and the other conditions are the same as those in Example 49. Compound 3aa (brown solid, 0.0710 g, yield 67%) was obtained by column chromatography.

[0218] The ee value of 3aa was obtained by HPLC analysis of its derivative reacted with di-tert-butyl dicarbonate, and its ee value was 96%.

[0219] Brown oil; [α] D 25 = +10.5 (c = 0.10, MeOH); 1 H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 7.6 Hz, 2H), 7.55 (d, J = 7.6 Hz, 2H), 7.47 - 7.39 (m, 4H), 7.33 (t, J = 7.2 Hz, 1H), 6.50 (d, J = 16.0 Hz, 1H), 6.31 - 6.20 (m, 1H), 4.51 (t, J = 4.8 Hz, 1H), 3.72 - 3.60 (m, 2H), 3.56 - 3.45 (m, 2H), 2.95 - 2.85 (m, 1H), 2.47 - 2.36 (m, 1H), 2.24 - 2.13 (m, 1H), 1.84 - 1.64 (m, 2H), 1.63 - 1.36 (m, 4H), 1.21 (t, J = 7.2 Hz, 6H); 13 C NMR (100 MHz, CDCl3) δ 140.8, 140.0, 136.5, 132.3, 128.9, 127.6, 127.3, 127.0, 126.6, 103.1, 61.3, 61.1, 51.1, 41.8, 32.7, 30.5, 15.5; HRMS (ESI): m / z Calcd. For C 23 H 32 NO2 (M + H) + : 354.2428; Found: 354.2430.

[0220] Example 76: Synthesis of compound 3ab

[0221]

[0222] The addition amounts of each component reagent and the reaction steps are referred to Example 49. Compared with Example 49, the difference is only that 1 g of [substituted 1a] is used instead, and the other conditions are the same as those in Example 49. Compound 3ab (pale yellow solid, 0.0862 g, yield 86%) was obtained by column chromatography.

[0223] The ee value of 3ab was obtained by HPLC analysis of its derivative reacted with di-tert-butyl dicarbonate, and its ee value was 95%.

[0224] Pale yellow solid; M.p. 81 - 83 °C; [α] D25 = +29.3 (c = 0.10, MeOH); 1 H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 7.6 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H), 7.47 - 7.39 (m, 4H), 7.33 (t, J = 7.6 Hz, 1H), 6.50 (d, J = 15.6 Hz, 1H), 6.28 - 6.17 (m, 1H), 3.69 - 3.58 (m, 1H), 3.47 - 3.30 (m, 2H), 3.28 - 3.17 (m, 1H), 2.92 - 2.81 (m, 1H), 2.45 - 2.35 (m, 3H), 2.29 - 2.18 (m, 1H), 2.09 - 1.96 (m, 2H), 1.77 - 1.69 (m, 3H), 1.55 - 1.43 (m, 1H); 13 C NMR (100 MHz, CDCl3) δ 175.4, 140.8, 140.1, 136.4, 132.6, 128.9, 127.4, 127.2, 127.0, 126.6, 48.5, 47.3, 41.9, 39.8, 34.9, 31.1, 18.0; HRMS (ESI): m / z Calcd. For C 22 H 27 N2O (M + H) + : 335.2118; Found: 335.2121.

[0225] Example 77: Synthesis of Compound 3ac

[0226]

[0227] The addition amounts of each component reagent and the reaction steps are shown in Example 49. Compared with Example 49, the difference is only that 1h is used to replace 1a and 2p is used to replace 2a, and the other conditions are the same as those in Example 49. Compound 3ac (orange oil, 0.0760 g, yield 87%) was obtained by column chromatography.

[0228] The ee value of 3ac was obtained by HPLC analysis of its derivative reacted with di-tert-butyl dicarbonate, and its ee value was 91%.

[0229] Orange oil; [α] D 25 = +8.9 (c = 0.10, MeOH); 11H NMR (400 MHz, CDCl3) δ 7.33 - 7.28 (m, 1H), 6.37 - 6.31 (m, 1H), 6.25 (d, J = 15.6 Hz, 1H), 6.19 - 6.13 (m, 1H), 6.11 - 6.01 (m, 1H), 4.02 - 3.90 (m, 2H), 3.80 - 3.70 (m, 1H), 3.70 - 3.61 (m, 1H), 3.05 - 2.94 (m, 1H), 2.52 - 2.38 (m, 1H), 2.36 - 2.23 (m, 1H), 2.10 - 1.98 (m, 1H), 1.56 (brs, 2H), 1.42 (s, 9H); 13 13C NMR (100 MHz, CDCl3) δ 156.4, 152.6, 141.8, 125.1, 121.8, 111.3, 107.1, 79.5, 54.2, 52.3, 51.5, 38.9, 35.0, 28.5; HRMS (ESI): m / z Calcd. For C 16 H 25 N2O3 (M + H) + : 293.1860; Found: 293.1861.

[0230] Example 78: Synthesis of Compound 3ad

[0231]

[0232] The addition amounts of each component reagent and the reaction steps are shown in Example 49. Compared with Example 49, the difference is only that 1i is used to replace 1a and 2b is used to replace 2a, and the other conditions are the same as those in Example 49. Compound 3ad (orange oil, 0.0356 g, yield 67%) was obtained by column chromatography.

[0233] The ee value of 3ad was obtained by HPLC analysis of its derivative reacted with thiocarbonyl diimidazole, and its ee value was 96%.

[0234] Pale yellow solid; M.p. 111 - 113 °C; [α] D 25 = +16.0 (c = 0.10, MeOH); 11H NMR (400 MHz, CD3OD) δ 7.38 (d, J = 7.2 Hz, 2H), 7.28 (t, J = 7.2 Hz, 2H), 7.19 (t, J = 7.6 Hz, 1H), 6.50 (d, J = 16.0 Hz, 1H), 6.33 - 6.21 (m, 1H), 3.64 - 3.57 (m, 1H), 3.47 - 3.39 (m, 1H), 3.03 - 2.92 (m, 1H), 2.47 - 2.36 (m, 1H), 2.31 - 2.20 (m, 1H); 13 13C NMR (100 MHz, CD3OD) δ 138.8, 134.2, 129.5, 128.2, 127.19, 127.16, 66.4, 53.9, 37.6; HRMS (ESI): m / z Calcd. For C 11 H 16 NO (M + H) + : 178.1226; Found: 178.1227.

[0235] Example 79: Synthesis of Compound 3ae

[0236]

[0237] The addition amounts of each component reagent and the reaction steps are referred to Example 49. Compared with Example 49, the difference is only that 1j is used to replace 1a, and the other conditions are the same as those in Example 49. Compound 3ae (colorless oil, 0.0460 g, yield 52%) was obtained by column chromatography.

[0238] The ee value of 3ae was obtained by HPLC analysis of its derivative reacted with di-tert-butyl dicarbonate, and its ee value was 92%.

[0239] Colorless oil; [α] D 25 = +4.9 (c = 0.10, MeOH); 1 1H NMR (400 MHz, CD3OD) δ 7.61 (d, J = 7.6

[0240] Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.42 (t, J = 8.0 Hz, 2H), 7.31 (t, J = 7.6 Hz, 1H), 6.53 (d, J = 15.6 Hz, 1H), 6.38 - 6.24 (m, 1H), 3.58 (t, J = 6.0 Hz, 2H), 3.02 - 2.91 (m, 1H), 2.50 - 2.40 (m, 1H), 2.35 - 2.23 (m, 1H), 1.65 - 1.40 (m, 6H);13 C NMR (100 MHz, CD3OD) δ 142.0, 141.2, 137.8, 133.9, 129.9, 128.3, 128.0, 127.72, 127.69, 127.5, 62.7, 52.2, 41.0, 36.9, 33.6, 23.3; HRMS (ESI): m / z Calcd. For C 20 H 26 NO (M + H) + : 296.2009; Found: 296.2012.

[0241] Example 80: Synthesis of Compound 3af

[0242]

[0243] The addition amounts of each component reagent and the reaction steps are shown in Example 49. Compared with Example 49, the difference is only that 1k is used to replace 1a and 2p is used to replace 2a, and the other conditions are the same as those in Example 49. Compound 3af (brown oil, 0.0670 g, yield 80%) was obtained by column chromatography.

[0244] The ee value of 3af was obtained by HPLC analysis of its derivative reacted with di-tert-butyl dicarbonate, and its ee value was 93%.

[0245] Brown oil; [α] D 25 = +13.6 (c = 0.10, MeOH); 1 H NMR (400 MHz, CDCl3) δ 7.33 - 7.28 (m, 1H),

[0246] 6.37 - 6.32 (m, 1H), 6.26 (d, J = 16.4 Hz, 1H), 6.18 - 6.14 (m, 1H), 6.14 - 6.04 (m, 1H), 5.12 (brs, 1H), 3.40 - 3.25 (m, 1H), 3.25 - 3.14 (m, 1H), 2.97 - 2.86 (m, 1H), 2.39 - 2.29 (m, 1H), 2.21 - 2.10 (m, 1H), 1.73 - 1.61 (m, 4H), 1.44 (s, 9H); 13 C NMR (100 MHz, CDCl3) δ 156.3, 152.8, 141.7, 125.9, 121.5, 111.3, 106.9, 79.3, 49.6, 42.3, 38.4, 37.3, 28.6; HRMS (ESI): m / z Calcd. For C 15 H 25N2O3(M+H) + : 281.1860; Found: 281.1863.

[0247] Example 81: Synthesis of Compound 3ag

[0248]

[0249] The addition amounts of each component reagent and the reaction steps are shown in Example 49. Compared with Example 49, the difference is only that 1k is used to replace 1a, 2s is used to replace 2a, the dosage of DFO is increased to 20 mol%, and the ligand (S,S a )-L6 is used, and the other conditions are the same as those in Example 49. Compound 3ag (yellow oil, 0.0623 g, yield 67%) was obtained by column chromatography.

[0250] The ee value of 3ag was obtained by HPLC analysis of its derivative reacted with benzoyl chloride, and its ee value was 92%.

[0251] Yellow oil; [α] D 25 = -10.1 (c = 0.10, MeOH); 1 H NMR (400 MHz, CDCl3) δ 6.12 - 5.91 (m, 2H),

[0252] 5.66 - 5.56 (m, 1H), 5.54 - 5.43 (m, 1H), 5.14 (brs, 1H), 3.39 - 3.24 (m, 1H), 3.24 - 3.10 (m, 1H), 2.91 - 2.76 (m, 1H), 2.27 - 2.16 (m, 1H), 2.11 - 1.97 (m, 3H), 1.70 - 1.57 (m, 1H), 1.50 - 1.20 (m, 18H), 0.88 (t, J = 6.4 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 156.3, 133.9, 133.7, 130.0, 127.9, 79.2, 49.8, 42.1, 38.4, 37.2, 32.7, 31.6, 29.1, 28.6, 22.7, 14.2; HRMS (ESI): m / z Calcd. For C 18 H 35 N2O2(M+H) + : 311.2693; Found: 311.2697.

[0253] Example 82: Synthesis of Compound 3ah

[0254]

[0255] The addition amounts of each component reagent and the reaction steps are shown in Example 49. Compared with Example 49, the only difference is that 1l is used instead of 1a, and 2p is used instead of 2a, and the other conditions are the same as those in Example 49. Compound 3ag (orange oil, 0.0714 g, yield 60%) was obtained by column chromatography.

[0256] The dr value of 3ah was obtained by HPLC analysis of its derivative reacted with cyclohexanecarbonyl chloride, and its dr value was 97:3.

[0257] orange oil;[α] D 25 =+33.00 (c = 0.10, MeOH); 1 H NMR (400 MHz, CD3OD) δ 7.40 - 7.36 (m,

[0258] 1H), 6.40 - 6.31 (m, 2H), 6.24 - 6.12 (m, 2H), 3.71 - 3.59 (m, 2H), 3.57 - 3.49 (m, 1H), 2.97 - 2.89 (m, 1H), 2.59 - 2.49 (m, 1H), 2.29 - 2.17 (m, 1H); 13 C NMR (100 MHz, CD3OD) δ 154.3, 142.8, 126.7, 122.7, 112.1, 107.7, 75.4, 64.7, 54.5, 37.0; HRMS (ESI): m / z Calcd. For C 10 H 16 NO3 (M + H) + : 198.1125; Found: 198.1128.

[0259] Example 83: Synthesis of compound 3ai

[0260]

[0261] The addition amounts of each component reagent and the reaction steps are shown in Example 49. Compared with Example 49, the only difference is that 1m is used instead of 1a, and 2e is used instead of 2a, and the other conditions are the same as those in Example 49. Compound 3ai (orange oil, 0.0450 g, yield 53%) was obtained by column chromatography.

[0262] The dr value of 3ai was obtained by HPLC analysis of its derivative reacted with di - tert - butyl dicarbonate, and its dr value was 99:1.

[0263] Orange oil; [α] D 25 =+43.3 (c = 0.10, MeOH);1 1H NMR (400 MHz, CDCl3) δ 7.32 (t, J = 7.2 Hz,

[0264] 2H), 7.27 (d, J = 7.6 Hz, 2H), 7.25 - 7.19 (m, 3H), 6.84 (d, J = 8.0 Hz, 2H), 6.35 (d, J = 15.6 Hz, 1H), 6.07 - 5.95 (m, 1H), 3.80 (s, 3H), 3.05 - 2.95 (m, 1H), 2.79 - 2.68 (m, 1H), 2.35 - 2.23 (m, 1H), 2.07 - 1.93 (m, 1H), 1.54 (brs, 2H), 1.33 (d, J = 6.4 Hz, 3H); 13 13C NMR (100 MHz, CDCl3) δ 158.9, 145.3, 132.0, 130.4, 128.5, 127.9, 127.2, 126.4, 125.6, 114.0, 56.7, 55.4, 45.7, 39.3, 16.7; HRMS (ESI): m / z Calcd. For C 19 H 24 NO (M + H) + : 282.1852; Found: 282.1855.

[0265] Example 84: Synthesis of Compound 3aj

[0266]

[0267] The addition amounts of each component reagent and the reaction steps are referred to Example 49. Compared with Example 49, the difference is only that 1n is used to replace 1a and 2e is used to replace 2a, and the other conditions are the same as those in Example 49. Compound 3aj (pale yellow oil, 0.0786 g, yield 87%) was obtained by column chromatography.

[0268] The dr value of 3aj was obtained by HPLC analysis of its derivative reacted with di - tert - butyl dicarbonate, and its dr value was 97:3.

[0269] Pale yellow oil; [α] D 25 = +42.0 (c = 0.10, MeOH); 1 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J =

[0270] 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 6.40 (d, J = 15.6 Hz, 1H), 6.11 - 6.01 (m, 1H), 5.14 - 5.06 (m, 1H), 3.80 (s, 3H), 3.00 - 2.90 (m, 1H), 2.40 - 2.30 (m, 1H), 2.12 - 1.88 (m, 3H), 1.68 (s, 3H), 1.64 - 1.54 (m, 4H), 1.44 - 1.27 (m, 4H), 1.28 - 1.08 (m, 2H), 0.92 (d, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 158.9, 132.1, 131.4, 130.4, 127.3, 125.4, 124.9, 114.0, 55.4, 48.7, 45.5, 41.8, 36.8, 29.5, 25.9, 25.5, 20.4, 17.8; HRMS (ESI): m / z Calcd. For C 20 H 32 NO (M + H) + : 302.2478; Found: 302.2482.

[0271] Example 85: Synthesis of Compound 3ak

[0272]

[0273] The addition amounts of each component reagent and the reaction steps are referred to Example 49. Compared with Example 49, the difference is only that 1n is used to replace 1a, 2s is used to replace 2a, the dosage of DFO is increased to 20 mol%, and the ligand (S,S a )-L6 is used, and the other conditions are the same as those in Example 49. Compound 3ak (brown oil, 0.0681 g, yield 78%) was obtained by column chromatography.

[0274] The dr value of 3ak was obtained by HPLC analysis of its derivative reacted with benzoyl chloride, and its dr value was 96:4.

[0275] Brown oil; [α] D 25 = +23.3 (c = 0.10, MeOH)); 1 H NMR (400 MHz, CDCl3) δ 6.11 - 5.94 (m, 2H),

[0276] 5.64 - 5.45 (m, 2H), 5.08 (t, J = 7.2 Hz, 1H), 2.93 - 2.80 (m, 1H), 2.27 - 2.17 (m, 1H), 2.08 - 1.88 (m, 7H), 1.67 (s, 3H), 1.59 (s, 3H), 1.57 - 1.48 (m, 1H), 1.42 - 1.21 (m, 8H), 1.19 - 1.05 (m, 2H), 0.92 - 0.83 (m, 6H); 13 C NMR (100 MHz, CDCl3) δ 133.6, 133.5, 131.3, 130.1, 128.3, 124.9, 48.8, 45.1, 41.1, 36.9, 32.7, 31.5, 29.4, 29.1, 25.8, 25.4, 22.6, 20.3, 17.8, 14.1; HRMS (ESI): m / z Calcd. For C 20 H 38 NO (M + H) + : 292.2999; Found: 292.3002.

[0277] Example 86: Synthesis of Compound 3al

[0278]

[0279] The addition amounts of each component reagent and the reaction steps are referred to Example 49. Compared with Example 49, the difference is only that 1o is used to replace 1a and 2e is used to replace 2a, and the other conditions are the same as those in Example 49. Compound 3al (orange oil, 0.1110 g, yield 88%) was obtained by column chromatography.

[0280] The dr value of 3al was obtained by HPLC analysis of its derivative reacted with di - tert - butyl dicarbonate, and its dr value was 98:2.

[0281] Orange oil; [α] D 25 = +18.8 (c = 0.10, MeOH); 1 H NMR (400 MHz, CDCl3) δ 7.27 (d, J = 8.0 Hz,

[0282] 2H), 6.82 (d, J = 7.6 Hz, 2H), 6.37 (d, J = 16.0 Hz, 1H), 6.08 - 5.97 (m, 1H), 4.32 - 4.19 (m, 1H), 4.10 - 3.98 (m, 1H), 3.78 (s, 3H), 3.07 - 2.96 (m, 1H), 2.47 - 2.36 (m, 1H), 2.36 - 2.23 (m, 2H), 2.20 - 2.09 (m, 1H), 1.84 (brs, 2H), 1.57 - 1.49 (m, 3H), 1.45 (s, 3H), 1.44 - 1.39 (m, 10H), 1.36 (s, 3H); 13 13C NMR (100 MHz, CDCl3) δ 170.4, 159.0, 132.2, 130.3, 127.2, 124.8, 114.0, 98.7, 80.7, 68.2, 66.3, 55.4, 49.2, 43.8, 42.7, 42.1, 36.8, 30.2, 28.2 19.9; HRMS (ESI): m / z Calcd. For C 24 H 38 NO5 (M + H) + : 420.2744; Found: 420.2751.

[0283] Example 87: Synthesis of Compound 3am

[0284]

[0285] The addition amounts of each component reagent and the reaction steps are referred to Example 49. Compared with Example 49, the difference is only that 1p is used to replace 1a and 2e is used to replace 2a, and the other conditions are the same as those in Example 49. Compound 3am (pale yellow oil, 0.0544 g, yield 73%) was obtained by column chromatography.

[0286] The dr value of 3am was obtained by HPLC analysis of its derivative reacted with di - tert - butyl dicarbonate, and its dr value was 98:2.

[0287] Pale yellow oil; [α] D 25 = +22.1 (c = 0.10, MeOH); 1 1H NMR (400 MHz, CDCl3) δ 7.27 (d, J =

[0288] 8.8Hz, 2H), 6.82 (d, J = 8.0Hz, 2H), 6.40 (d, J = 15.6Hz, 1H), 6.11 - 5.99 (m, 1H), 3.86 - 3.79 (m, 1H), 3.78 (s, 3H), 3.77 - 3.71 (m, 1H), 3.67 (q, J = 7.2Hz, 1H), 2.81 - 2.72 (m, 1H), 2.45 - 2.32 (m, 1H), 2.20 - 2.08 (m, 1H), 2.02 - 1.82 (m, 3H), 1.73 (brs, 2H), 1.67 - 1.56 (m, 1H); 13 13C NMR (100MHz, CDCl3) δ 158.9, 132.1, 130.3, 127.3, 124.8, 114.0, 83.2, 68.1, 55.40, 55.36, 38.3, 28.6, 26.3; HRMS (ESI): m / z Calcd. For C 15 H 22 NO2 (M + H) + : 248.1645; Found: 248.1646.

[0289] Example 88: Synthesis of Compound 3an

[0290]

[0291] The addition amounts of each component reagent and the reaction steps are referred to Example 49. Compared with Example 49, the only difference is that 1q is used to replace 1a, 2e is used to replace 2a, the dosage of DFO is increased to 10 mol%, and the ligand (S,S a )-L6 is used, and the remaining conditions are the same as those in Example 49. Compound 3an (white solid, 0.0706 g, yield 85%) was obtained by column chromatography.

[0292] The dr value of 3an was obtained by HPLC analysis of its derivative reacted with benzoyl chloride, and its dr value was 97:3.

[0293] White solid; M.p. 52 - 53 °C; [α] D 25 = -15.6 (c = 0.10, MeOH); 1 1H NMR (400MHz, CDCl3) δ

[0294] 7.29 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 6.41 (d, J = 15.6 Hz, 1H), 6.11 - 5.98 (m, 1H), 4.07 - 3.97 (m, 2H), 3.94 - 3.86 (m, 1H), 3.80 (s, 3H), 3.09 - 2.99 (m, 1H), 2.51 - 2.40 (m, 1H), 2.22 - 2.11 (m, 1H), 1.75 (brs, 2H), 1.44 (s, 3H), 1.36 (s, 3H); 13 13C NMR (100 MHz, CDCl3) δ 159.1, 132.5, 130.2, 127.3, 124.3, 114.1, 109.1, 79.3, 65.9, 55.4, 52.8, 37.8, 26.7, 25.4; HRMS (ESI): m / z Calcd. For C 16 H 24 NO3 (M + H) + : 278.1751; Found: 278.1753.

[0295] Example 89: Synthesis of Compound 3ao

[0296]

[0297] The addition amounts of each component reagent and the reaction steps are referred to Example 49. Compared with Example 49, the difference is only that 1q is used to replace 1a, 2s is used to replace 2a, the dosage of DFO is increased to 20 mol%, and the ligand (S,S a )-L6 is used, and the remaining conditions are the same as those in Example 49. Compound 3ao (brown oil, 0.0595 g, yield 74%) was obtained by column chromatography.

[0298] The dr value of 3ao was obtained by HPLC analysis of its derivative reacted with benzoyl chloride, and its dr value was 96:4.

[0299] Brown oil; [α] D 25 = +3.8 (c = 0.10, MeOH); 1 1H NMR (400 MHz, CDCl3) δ 6.14 - 5.94 (m, 2H),

[0300] 5.67 - 5.57 (m, 1H), 5.57 - 5.45 (m, 1H), 4.04 - 3.92 (m, 2H), 3.90 - 3.80 (m, 1H), 3.04 - 2.90 (m, 1H), 2.39 - 2.28 (m, 1H), 2.10 - 1.95 (m, 3H), 1.61 (brs, 2H), 1.42 (s, 3H), 1.40 - 1.37 (m, 1H), 1.35 (s, 3H), 1.33 - 1.22 (m, 5H), 0.88 (t, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 134.0, 133.8, 129.9, 127.4, 109.0, 79.2, 65.9, 52.8, 37.3, 32.7, 31.5, 29.1, 26.7, 25.4, 22.6, 14.1; HRMS (ESI): m / z Calcd. For C 16 H 30 NO2 (M + H) + : 268.2271; Found: 268.2276.

[0301] Example 90: Synthesis of Compound 3ap

[0302]

[0303] The addition amounts of each component reagent and the reaction steps are referred to Example 49. Compared with Example 49, the difference is only that 1q is used to replace 1a and 2p is used to replace 2a, and the other conditions are the same as those in Example 49. Compound 3ap (brown oil, 0.0638 g, yield 79%) was obtained by column chromatography.

[0304] The dr value of 3ap was obtained by HPLC analysis of its derivative reacted with di - tert - butyl dicarbonate, and its dr value was 99:1.

[0305] Brown oil; [α] D 25 = - 65.9 (c = 0.10, MeOH); 1 H NMR (400 MHz, CDCl3) δ 7.34 - 7.30 (m, 1H),

[0306] 7.13 - 7.01 (m, 2H), 6.89 - 6.78 (m, 2H), 6.38 - 6.29 (m, 2H), 6.23 - 6.12 (m, 2H), 3.95 - 3.85 (m, 1H), 3.06 - 2.97 (m, 1H), 2.91 - 2.83 (m, 1H), 2.83 - 2.74 (m, 1H), 2.64 - 2.51 (m, 1H), 2.40 - 2.27 (m, 1H), 2.05 - 1.96 (m, 1H), 1.96 - 1.63 (m, 3H); 13 C NMR (100 MHz, CDCl3) δ 155.0, 152.9, 141.7, 129.6, 127.3, 125.9, 122.2, 121.5, 120.3, 116.9, 111.3, 106.9, 78.7, 54.7, 37.6, 25.0, 24.4; HRMS (ESI): m / z Calcd. For C 17 H 20 NO2 (M + H) + : 270.1489; Found: 270.1491.

[0307] Example 91: Synthesis of Compound 3aq

[0308]

[0309] The addition amounts of each component reagent and the reaction steps are referred to Example 49. Compared with Example 49, the difference is only that 1r is used to replace 1a and 2e is used to replace 2a, and the remaining conditions are the same as those in Example 49. Compound 3aq (pale yellow solid, 0.1390 g, yield 89%) was obtained by column chromatography.

[0310] The dr value of 3aq was obtained by HPLC analysis of its derivative reacted with di - tert - butyl dicarbonate, and its dr value was 98:2.

[0311] Pale yellow solid; M.p. 75 - 77 °C; [α] D 25 = +46.3 (c = 0.10, MeOH); 1 H NMR (400 MHz, CDCl3)

[0312] δ 7.29 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 8.0 Hz, 2H), 6.39 (d, J = 16.0 Hz, 1H), 6.10 - 5.99 (m, 1H), 4.01 - 3.95 (m, 1H), 3.80 (s, 3H), 3.65 - 3.53 (m, 1H), 2.83 - 2.73 (s, 1H), 2.42 - 2.33 (m, 1H), 2.14 - 2.02 (m, 1H), 1.92 - 1.00 (m, 30H), 0.98 (d, J = 6.4 Hz, 3H), 0.90 (s, 3H), 0.67 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 158.9, 132.1, 130.4, 127.3, 125.3, 114.1, 73.3, 71.9, 55.4, 51.8, 48.4, 47.5, 46.6, 42.2, 41.5, 36.6, 36.1, 35.8, 35.3, 34.2, 33.8, 32.5, 30.6, 28.7, 27.7, 27.3, 26.3, 23.8, 23.3, 18.0, 12.9; HRMS (ESI): m / z Calcd. For C 34 H 54 NO3 (M + H) + : 524.4098; Found: 524.4101.

[0313] Example 92: Synthesis of Compound 3ar

[0314]

[0315] The addition amounts of each component reagent and the reaction steps are referred to Example 49. Compared with Example 49, the difference is only that 1s is used to replace 1a and 2u is used to replace 2a, and the remaining conditions are the same as those in Example 49. Compound 3aq (brown solid, 0.0638 g, yield 60%) was obtained by column chromatography.

[0316] The ee value of 3aq was obtained by HPLC analysis of its derivative reacted with di - tert - butyl dicarbonate, and its ee value was 97%.

[0317] Brown oil; [α] D 25 = +23.6 (c = 0.10, MeOH); 1 H NMR (400 MHz, CDCl3) δ 8.13 - 8.05 (m, 1H),

[0318] 7.70 - 7.62 (m, 1H), 7.52 - 7.44 (m, 1H), 7.32 - 7.24 (m, 1H), 6.72 (d, J = 2.2 Hz, 1H), 6.22 (d, J = 16.0 Hz, 1H), 6.00 - 5.96 (m, 1H), 3.50 - 3.43 (m, 1H), 2.36 - 2.22 (m, 1H), 2.04 - 1.96 (m, 1H), 1.80 (brs, 2H), 1.57 (s, 9H); 13 C NMR(100MHz, CDCl3) δ 150.5, 143.9, 137.9, 133.8, 129.1, 126.6, 123.3 (q, J = 280.0 Hz), 122.9, 122.5, 122.3, 116.4, 109.0, 83.5, 52.7 (q.J = 25.4 Hz), 38.4 (q, J = 2.1 Hz), 27.9; HRMS(ESI): m / z Calcd.For C 18 H 22 F3N2O2 (M + H) + : 355.1628, Found: 355.1625.

[0319] Example 93: Synthesis of Compound 3as

[0320]

[0321] The addition amounts of each component reagent and the reaction steps are referred to Example 49. Compared with Example 49, the difference is only that 1s is used to replace 1a and 2u is used to replace 2a, and the other conditions are the same as those in Example 49. Compound 3aq (white solid, 0.0495 g, yield 58%) was obtained by column chromatography.

[0322] The ee value of 3aq was obtained by HPLC analysis of its derivative reacted with di - tert - butyl dicarbonate, and its ee value was 93%.

[0323] White solid; 1 H NMR(400MHz, CDCl 3);δ 7.62 - 7.56 (m, 4H), 7.47 - 7.43 (m, 4H), 7.37 - 7.34 (m, 1H), 6.59 (d, J = 15.7 Hz, 1H), 6.26 (dt, J = 15.3, 7.3 Hz, 1H), 3.45 - 3.25 (m, 1H), 2.69 (dddd, J = 14.4, 7.1, 3.9, 1.5 Hz, 1H), 2.40 (dddd, J = 14.3, 9.0, 7.4, 1.3 Hz, 1H), 1.43 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 140.8, 140.5, 136.0, 133.7, 128.9, 126.6 (q, J = 279.9 Hz), 127.5, 127.4, 127.1, 126.8, 124.5, 53.7 (q, J = 28.3 Hz), 33.9 (q, J = 1.8 Hz); 19 F NMR (376 MHz, CDCl3) δ -78.15. HRMS m / z Calcd. for C 17 H 16 F3N (M + H) + : 292.1308; Found: 292.1307.

[0324] Example 94: Synthesis of compound 3at

[0325]

[0326] The addition amounts of each component reagent and the reaction steps are shown in Example 49. Compared with Example 49, the difference is only that 1s is used to replace 1a and 2v is used to replace 2a, and the other conditions are the same as those in Example 49. Compound 3at (colorless oil, 0.0540 g, yield 66%) was obtained by column chromatography.

[0327] The ee value of 3at was obtained by HPLC analysis of its derivative reacted with di-tert-butyl dicarbonate, and its ee value was 73%.

[0328] Colourless oil; 1 H NMR (400 MHz, CDCl3); δ 7.88 (dd, J = 13.6, 7.9 Hz, 2H), 7.42 (s, 1H),

[0329] 7.56 - 7.31 (m, 2H), 6.81 (d, J = 15.7 Hz, 1H), 6.28 (dt, J = 15.2, 7.3 Hz, 1H), 3.47 - 3.31 (M, 1H), 2.72 (ddd, J = 14.7, 7.1, 4.1 Hz, 1H), 2.45 (dt, J = 15.2, 8.2 Hz, 1H), 1.53 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 140.6, 137.7, 133.7, 126.6 (q, J = 279.8 Hz) 126.4, 126.2, 124.4, 124.4, 123.1, 122.0, 122.0, 53.7 (q, J = 28.6 Hz), 34.2 (q, J = 2.1 Hz); 19 19F NMR (376 MHz, CDCl3) δ -78.12. HRMS m / z Calcd. for C13H12F3NS (M + H) + : 272.0715; Found: 272.0715.

[0330] Example 95: Synthesis of compound 3au

[0331]

[0332] The addition amounts of each component reagent and the reaction steps are shown in Example 49. Compared with Example 49, the difference is only that 1t is used to replace 1a, and the other conditions are the same as those in Example 49. Compound 3au (brown solid, 0.0905 g, yield 82%) was obtained by column chromatography.

[0333] The ee value of 3au was obtained by HPLC analysis of its derivative reacted with di-tert-butyl dicarbonate, and its ee value was 95%.

[0334] Brown solid; 1 1H NMR (400 MHz, CDCl3); δ 7.63 - 7.58 (m, 2H), 7.55 - 7.34 (m, 2H), 7.35 - 7.28 (m, 4H), 7.35 - 7.28 (m, 3H), 6.69 (d, J = 9.0 Hz, 2H), 6.50 (dd, J = 30.0, 2H), 6.29 (dt, J = 16.0, 7.2 Hz, 2H), 6.06 (dd, J = 15.8, 6.8 Hz, 0H), 3.64 (q, J = 6.8 Hz, 1H), 2.96 (s, 6H), 2.58 - 2.47 (m, 1H), 2.42 (m, 1H); 1313C NMR(100MHz,CDCl3)δ150.1,140.9,140.0,136.6,132.3,130.0,129.2,128.9,127.4,127.3,127.0,126.7,125.7,112.6,54.1,42.1,40.7.HRMS m / z Calcd.for C 26 H 29 N2(M+H) + :369.2395;Found:369.2390.

[0335] Example 96: Synthesis of Compound 3av

[0336]

[0337] The addition amounts of each component reagent and the reaction steps are shown in Example 49. Compared with Example 49, the only difference is that 1u is used to replace 1a and 2w is used to replace 2a, and the other conditions are the same as those in Example 49. Compound 3av (brown solid, 0.0601 g, yield 70%) was obtained by column chromatography.

[0338] The ee value of 3av was obtained by HPLC analysis of its derivative reacted with di-tert-butyl dicarbonate, and its ee value was 95%.

[0339] Brown solid; 1 1H NMR(400MHz,CDCl3);δ7.38(q,J=7.6Hz,2H),7.32(t,J=7.6Hz,2H),

[0340] 7.23(t,J=7.4Hz,1H),6.85-6.75(m,2H)6.56(dd,J=15.8,9.6Hz,2H),6.24(dd,J=15.8,7.0Hz,2H),3.67(q,J=7.0,2H),2.56-2.49(m,1H),2.48–2.36(m,2H),1.63(s,2H); 1313C NMR(100MHz,CDCl3)δ162.0(dd,J=247,11.9Hz),160.1(dd,J=250,11.6Hz),137.1,134.0,129.5,129.2(dd,J=4.7,2.2Hz),128.7,128.1(dd,J=9.4,5.4Hz),127.6,126.5,124.5(dd,J=3.3,1.5Hz),121.6(dd,J=12.6,3.9Hz),111.4(dd,J=21.3,3.6Hz),104.1(t,J=25.7Hz),53.8,42.1.HRMS m / z Calcd.for C 18 H 18 F2N(M+H) + :286.1402;Found:286.1400.

[0341] Example 97: Synthesis of Compound 3aw

[0342]

[0343] The addition amounts of each component reagent and the reaction steps are referred to Example 49. Compared with Example 49, the difference is only that 1v is used to replace 1a and 2e is used to replace 2a, and the other conditions are the same as those in Example 49. Compound 3aw (brown solid, 0.0581 g, yield 68%) was obtained by column chromatography.

[0344] The ee value of 3aw was obtained by HPLC analysis of its derivative reacted with di-tert-butyl dicarbonate, and its ee value was 96%.

[0345] Brown solid; 1 1H NMR(400MHz,CDCl3);δ7.38(q,J=7.6Hz,2H),7.32(t,J=7.6Hz,2H),

[0346] 7.23(t,J=7.4Hz,1H),6.85-6.75(m,2H)6.56(dd,J=15.8,9.6Hz,2H),6.24(dd,J=15.8,7.0Hz,2H),3.67(q,J=7.0,2H),2.56-2.49(m,1H),2.48–2.36(m,2H),1.63(s,2H); 1313C NMR (100 MHz, CDCl3) δ 162.0 (dd, J = 247, 11.9 Hz), 160.1 (dd, J = 250, 11.6 Hz), 137.1, 134.0, 129.5, 129.2 (dd, J = 4.7, 2.2 Hz), 128.7, 128.1 (dd, J = 9.4, 5.4 Hz), 127.6, 126.5, 124.5 (dd, J = 3.3, 1.5 Hz), 121.6 (dd, J = 12.6, 3.9 Hz), 111.4 (dd, J = 21.3, 3.6 Hz), 104.1 (t, J = 25.7 Hz), 53.8, 42.1. HRMS m / z Calcd. for C 18 H 18 F2N(M + H) + : 286.1402; Found: 286.1400.

[0347] Example 98: Synthesis of Compound 3ax

[0348]

[0349] The addition amounts of each component reagent and the reaction steps are shown in Example 49. Compared with Example 49, the difference is only that 1w is used to replace 1a, and the remaining conditions are the same as those in Example 49. Compound 3aw (yellow solid, 0.0792 g, yield 70%) was obtained by column chromatography.

[0350] The ee value of 3ax was obtained by HPLC analysis of its derivative reacted with di-tert-butyl dicarbonate, and its ee value was 93%.

[0351] Brown solid; 1 1H NMR (400 MHz, CDCl3) δ 7.79 - 7.71 (m, 2H), 7.64 - 7.55 (m, 4H), 7.55 - 7.49 (m, 2H), 7.49 - 7.40 (m, 2H), 7.38 - 7.29 (m, 3H), 6.29 (d, J = 15.0 Hz, 1H), 6.00 - 5.89 (m, 1H), 4.01 - 3.89 (m, 1H), 3.30 (s, 3H), 2.63 - 2.57 (m, 1H), 2.44 - 2.32 (m, 1H), 2.37 (brs, 1H); 1313C NMR(100MHz,CDCl3)δ146.7,144.5,144.2,140.8,139.1,129.6,128.8,127.7,127.4,127.2,127.0,126.4,126.3,124.9,56.7,44.6,36.9.HRMS m / z Calcd.for C 23 H 24 NO2S(M+H) + :378.1522;Found:378.1520.

[0352] The above description of the embodiments is provided to enable those of ordinary skill in the art to understand and use the invention. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative efforts. Therefore, the present invention is not limited to the above embodiments, and all improvements and modifications made by those skilled in the art without departing from the scope of the present invention as disclosed should be within the protection scope of the present invention.

Claims

1. A method for synthesizing homoallylamine, characterized in that, Using an unprotected primary amine compound and an allylation reagent as raw materials, under the catalysis of a carbonyl catalyst and a metal catalyst, a homoallylic amine is obtained.

2. The synthesis method of a homoallylamine according to claim 1, characterized in that, The structure of the unprotected primary amine compound is: Among them, R 1 is selected from any one of alkyl, substituted alkyl substituted with any number of substituents, cycloalkyl having at least one heteroatom in the ring, substituted aryl substituted with any number of substituents, substituted heteroaryl substituted with any number of substituents, substituted alkenyl substituted with any number of substituents, and substituted alkynyl substituted with any number of substituents.

3. The synthesis method of a homoallylamine according to claim 2, characterized in that, R 1 The substituents in 1 are selected from halogen, C1-C10 alkyl, C1-C10 alkoxy, aryl, haloalkyl, nitro, alkoxycarbonyl, amido, ketocarbonyl, aldehyde group, protected or unprotected hydroxy group, protected or unprotected amino group; the heteroatom is selected from O, S, NH or NRp, and Rp is an amino protecting group.

4. A method for synthesizing homoallylamine according to claim 1, characterized in that, The structure of the allylation reagent is: Among them, R 2 , R 3 , R 4 are independently selected from H, aryl, substituted aryl or heteroaryl substituted by any number of Rn, alkyl alkenyl, and substituted alkyl alkenyl substituted by any number of Rn; Rn is selected from any one of halogen, C1-C10 alkyl, C1-C10 alkoxy, aryl, haloalkyl, nitro; The heteroatom of the heteroaryl is selected from O, S, NH or NRp, and Rp is an amino protecting group; PG is selected from tert-butoxycarbonyl, benzyloxycarbonyl, ethyloxycarbonyl, methyloxycarbonyl, acetyl, phosphate group.

5. A method for synthesizing homoallylamine according to claim 1, characterized in that, The carbonyl catalyst is 1,8-diazafluorenone; The metal catalyst is any one of [Ir(COD)Cl]2, Ir(COD)2BF4, Ir(acac)(CO)2, [Ir(CH2CH2)2Cl]2, Ir(PPh3)2(CO)Cl, [Ir(COD)(OMe)]2, [Ir(COE)2Cl]2, [Ir(acac)(COD)], or [Ir(hfac)(COD)]; 6. The synthesis method of a homoallylamine according to claim 1, characterized in that, The molar ratio of the allylation reagent, the unprotected primary amine compound, the carbonyl catalyst and the metal catalyst is 1:(0.50 - 5.0):(0.01 - 0.20):(0.01 - 0.10).

7. A method for synthesizing homoallylamine according to claim 1, characterized in that, A ligand is also added during the reaction, and its molar ratio to the allylation reagent is (0.01 - 0.2):1, and it is selected from any one of the following structures: and its enantiomeric structure; Wherein, R 5 or R 7 is an independently substituted or unsubstituted C4-C 15 aryl group, and the substituents include C1-C8 alkyl group, C4-C 15 aryl group, protected amino group, hydroxyl group, halogen, nitro group, cyano group; R 6 Independently selected from cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cyclotetradecyl, cyclopentadecyl, cyclohexadecyl, diphenylmethyl, dicyclohexylmethyl.

8. A method for synthesizing homoallylamine according to claim 1, characterized in that, A base is also added during the reaction, and its molar ratio to the allylation reagent is (0.10 - 5.00):

1. The base is at least one of sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, calcium hydride, potassium fluoride, triethylamine, diisopropylamine, diisopropylethylamine, tetramethylethylenediamine, N,N-dimethylaniline, N,N-diethylaniline, 1,4-diazabicyclooctane, tetramethylguanidine, diazabicyclododecane, n-butyllithium, 1,4-dimethylpiperazine, 1-methylpiperidine, 1-methylpyrrole, quinoline or pyridine.

9. A method for synthesizing homoallylamine according to claim 1, characterized in that, An additive is also added during the reaction, and it is selected from any one of zinc fluoride, zinc chloride, zinc bromide, zinc iodide, zinc phosphate, zinc hydroxide, zinc carbonate, zinc benzoate, zinc trifluoroacetate, zinc p-toluenesulfonate, silver trifluoromethanesulfonate, copper trifluoromethanesulfonate, iron trifluoromethanesulfonate, scandium trifluoromethanesulfonate, calcium bromide, copper bromide, cuprous bromide, iron bromide or magnesium bromide; The molar ratio of the additive to the allylation reagent is (0.10 - 5.00):

1.

10. A method for synthesizing homoallylamine according to claim 1, characterized in that, The reaction process is carried out in a solvent system, and the solvents used are at least one of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, cyclohexyl methyl ether, ethylene glycol dimethyl ether, ethylene glycol monomethyl ether, water, methanol, ethanol, n-propanol, isopropanol, n-butanol, trifluoroethanol, benzene, toluene, xylene, mesitylene, acetonitrile, dichloromethane, chloroform, N,N–dimethylformamide, N,N–dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone; The reaction temperature is 0 - 50 °C and the time is 1 - 72 h.

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