A synthesis method and application of chiral semicorrin compound

Abstract

The present invention uses organic magnesium bromide as a substrate to react with various optically pure amino acid ester hydrochlorides to obtain chiral hemicorin compounds with diverse structures. The method has readily available raw materials and is simple to operate, and provides a new synthetic strategy for the construction of chiral hemicorin derivatives. #imgabs0##imgabs1#

Description

Technical Field

[0001] The invention relates to the technical field of medicine and organic chemical synthesis, and in particular to a synthesis method and application of a chiral semicorrin compound. Background Art

[0002] In the past fifty years, metal-catalyzed coupling reactions have been shining on the chemical stage and are widely used in the synthesis process of materials, medicine and other fields. The arylation of aldehydes is one of the most important reactions for building carbon-carbon bonds. Traditional arylation methods use aryl lithium or Grignard reagents as arylating agents. So far, the metal-catalyzed coupling reaction of aldehydes with organic halides is the main method to obtain chiral alcohols. This method usually uses nickel-catalyzed reactions between aryl bromides and aldehydes to obtain chiral diarylmethanols. Professor Cheng used [NiBr2-(dppe)] / Zn to couple aryl bromides and aromatic aldehydes ( Org. Lett. ,2000, 2 , 2295.), can obtain aromatic alcohols with high yields and good chemical selectivity; but when the chiral bisoxazoline compound (4S,4'S)-2,2'-(pentane-3,3-diyl)bis(4-phenyl-4,5-dihydrooxazole) is used as a ligand, the product has no enantioselectivity. The study pointed out that the choice of ligand is the key to the catalytic synthesis of secondary alcohols. Subsequently, scientists combined nickel salts with the chiral bisoxazoline ligand (4S,4'S)-2,2'-(propane-2,2-diyl)bis(4-phenyl-4,5-dihydrooxazole) and developed an asymmetric reduction coupling reaction, which gave the obtained secondary alcohols moderate enantioselectivity ( Eur. J. Org. Chem., 2019, 7483). In addition, Professor Shi Zhuangzhi of Nanjing University used the chiral bis-oxazoline compound 2,2-bis((4R,5S)-4,5-diphenyl-4,5-dihydrooxazol-2-yl)acetonitrile combined with nickel salt to catalyze the intermolecular enantioselective addition of aryl iodide to aromatic aldehydes with good yield and excellent ee The corresponding chiral secondary alcohols ( Angew. Chem. Int. Ed., 2022, e202201370. doi. org / 10.1002 / anie. 202201370.).

[0003] Chiral bisoxazoline ligands have become one of the most important ligands in the current field of asymmetric catalytic synthesis research due to their structural diversity, easy availability of chiral sources, good chiral induction ability, and their ability to complex with transition metals to efficiently catalyze a variety of asymmetric reactions.

[0004] Since Evans and Jacobsen successfully applied C-2 symmetric chiral bisoxazoline ligands to asymmetric catalysis ( J. Am. Chem. Soc., 1991, 113 , 726), several research groups introduced new functional groups on the carbon bridge of the bisoxazoline ligand to design and synthesize a series of new chiral bisoxazoline ligands. These ligands can not only effectively improve the stereo control ability of the catalyst and broaden the scope of application, but also often have bifunctional properties. For example, Tang Yong's research group at the Shanghai Institute of Organic Chemistry designed a series of new chiral bisoxazoline ligands based on the concept of designing metal organic catalysts using the side-arm strategy, and successfully applied them to more than 20 important asymmetric catalytic reactions ( Acc. Chem. Res., 2014, 47 , 2260). Xiao Wenjing's research group at Central China Normal University designed a class of bifunctional bis-oxazoline ligands containing photosensitive groups based on the concept of light / transition metal catalysis, and achieved excellent results in asymmetric oxidation reactions catalyzed by light / nickel ( J. Am. Chem. Soc., 2017, 139 ,63). Through experiments, we found that compared with neutral bisoxazoline ligands, anionic ligands can not only enhance the stability and nucleophilicity of metal complexes, but also effectively regulate the redox properties of nickel complexes through newly introduced functional groups, which helps to promote nickel-catalyzed reductive coupling reactions.

[0005] After introducing an electron-withdrawing group at the bridge carbon position of the bisoxazoline, a semicorrin ligand is formed. After experiments, it was found that the chiral semicorrin ligand can effectively promote the asymmetric reductive arylation of aldehydes and bromides, which can effectively improve the yield and ee value. However, there is no method for synthesizing such ligands so far. The present invention provides a relatively simple and efficient method for synthesizing chiral semicorrin molecules, and obtains chiral semicorrin molecules with different groups by synthesizing amino alcohols with different structures, thereby effectively improving the catalytic efficiency and expanding the application range of chiral semicorrin ligands. Summary of the invention

[0006] In order to overcome the shortcomings and deficiencies of the prior art, the object of the present invention is to provide a method for synthesizing chiral hemicorrin compounds. The present invention uses organic magnesium bromide as a substrate and reacts with various optically pure amino acid ester hydrochlorides to obtain chiral hemicorrin compounds with diverse structures. The method has readily available raw materials and is simple to operate, providing a new synthetic strategy for the construction of chiral hemicorrin derivatives. The implementation of the method relies on the participation of diethyl malonimide dihydrochloride, which is prepared by passing hydrogen chloride gas through malononitrile and ethanol in a dioxane solvent, and the reaction equation is:

[0007]

[0008] Among them, according to the systematic nomenclature, the atomic order of oxazoline is shown in the following formula:

[0009]

[0010] The purpose of the present invention is achieved through the following technical solutions:

[0011] ① Through organic magnesium bromide and D The method for synthesizing a C-5 substituted chiral hemicorin compound from -phenylglycine methyl ester hydrochloride comprises the following steps:

[0012] First, in an inert gas atmosphere, organic magnesium bromide and D -phenylglycine methyl ester hydrochloride was refluxed in ether and subsequently treated to obtain (R) -2-amino-1,1-disubstituted-2-phenyl-1-ol A. Next, A and diethyl malonimide dihydrochloride were refluxed in dichloromethane, and the C-5 substituted chiral bisoxazoline compound B was obtained after subsequent treatment. Finally, B and 4-toluenesulfonyl cyanide were reacted in the presence of n-butyl lithium, N,N,N',N' -tetramethylethylenediamine and tetrahydrofuran to react, and after treatment, a chiral hemicorin compound C is obtained.

[0013] The structure of the organic magnesium bromide is

[0014] R 1 -MgBr

[0015] In its structure, "R 1 ” is: methyl, 1-naphthyl, 4-fluorophenyl, 4-methylphenyl, etc.

[0016] The organic magnesium bromide and D -phenylglycine methyl ester hydrochloride has a molar ratio of 6:1.

[0017] The molar ratio of A to diethyl malonimide dihydrochloride is 2.1:1.

[0018] The molar ratio of B to 4-toluenesulfonyl cyanide is 1:1.12. The molar ratio of B to n-butyl lithium is 1:1.1. N, N,N',N' -tetramethylethylenediamine, the molar ratio is 1:1.17.

[0019] The subsequent treatment refers to cooling, concentrating and purifying the product after the reaction by column chromatography.

[0020] The eluent of the column chromatography is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is (5-100):1.

[0021] The structure of the C-5 substituted chiral hemicorin compound is

[0022]

[0023] The reaction equation of method 1 is:

[0024]

[0025]

[0026]

[0027] ② A method for synthesizing a C-4 substituted chiral hemicorin compound by organic magnesium bromide and amino acid ester hydrochloride, comprising the following steps:

[0028] Step 1: Bromide and magnesium turnings are reacted in tetrahydrofuran with 1,2-dibromoethane to generate a Grignard reagent, which then reacts with diethyl oxalate to obtain product D.

[0029] Step 2: D and ( R) -tert-Butylsulfenamide reacts under the action of tetraisopropyl titanate to obtain product E in tetrahydrofuran solution.

[0030] Step 3: At -78 °C, lithium tri-sec-butylborohydride is used in tetrahydrofuran to reduce the carbon-nitrogen double bond of E to obtain product F.

[0031] Step 4: Add hydrogen chloride / dioxane to the methanol solution of F to obtain product G.

[0032] Step 5: G is reacted with phenylmagnesium bromide in ether under reflux to obtain amino acid ester hydrochloride H.

[0033] Step 6: Reflux H and diethyl malonimide dihydrochloride in dichloromethane, and obtain C-4 substituted chiral bis-oxazoline compound I after subsequent treatment.

[0034] Step 7: I and 4-toluenesulfonyl cyanide in n-butyl lithium, N,N,N',N' -tetramethylethylenediamine and tetrahydrofuran to react and obtain chiral hemicorin compound J after treatment.

[0035] The structure of the phenyl bromide is

[0036] R 2 Br

[0037] In its structure, "R 2 ” is: 3,5-di-tert-butylphenyl, 3,5-diphenylphenyl, 3,5-bistrifluoromethylphenyl, 3,5-di-tert-butyl-4-methoxyphenyl, 1-naphthyl, etc.

[0038] In step 1, the molar ratio of bromide to magnesium and 1,2-dibromoethane is 1:1.3:0.12; the molar ratio of bromide to diethyl oxalate is 1:2.

[0039] Step 2 D and ( R) The molar ratio of D to tetraisopropyl titanate is 1:1.

[0040] In step 3, the molar ratio of E to lithium tri-sec-butylborohydride is 1:1.1.

[0041] In step 4, the molar ratio of F to hydrogen chloride / dioxane is 1:4.

[0042] In step 5, the molar ratio of G to phenylmagnesium bromide is 1:6.

[0043] In step 6, the molar ratio of H to diethyl malonimide dihydrochloride is 2.1:1.

[0044] In step 7, the molar ratio of I to 4-toluenesulfonyl cyanide is 1:1.12; the molar ratio of I to n-butyl lithium is 1:1.1; N,N,N',N' -The molar ratio of tetramethylethylenediamine is 1:1.17;

[0045] The subsequent treatment refers to cooling, concentrating and purifying the product after the reaction by column chromatography.

[0046] The eluent of the column chromatography is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is (5-100):1.

[0047] The structure of the C-4 substituted chiral hemicorin compound is

[0048]

[0049] The reaction equation of method 2 is:

[0050]

[0051]

[0052]

[0053]

[0054] Compared with the existing technology, the present invention has the following advantages and effects:

[0055] The invention successfully synthesizes chiral semicorrin compounds, uses low-cost and easily available raw materials, has safe operation, strong functional group tolerance, a wide range of substrate universality, and mild reaction conditions. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Figure 1 is the hydrogen spectrum of the product obtained in Example 1;

[0057] Figure 2 is the carbon spectrum of the product obtained in Example 1;

[0058] Figure 3 is the hydrogen spectrum of the product obtained in Example 2;

[0059] Figure 4 is the carbon spectrum of the product obtained in Example 2;

[0060] Figure 5 is the fluorine spectrum of the product obtained in Example 2;

[0061] Figure 6 is the hydrogen spectrum of the product obtained in Example 3;

[0062] Figure 7 is the carbon spectrum of the product obtained in Example 3;

[0063] Figure 8 is the hydrogen spectrum of the product obtained in Example 4;

[0064] Fig. 9 is the carbon spectrum of the product obtained in Example 4;

[0065] Fig.10 is the hydrogen spectrum of the product obtained in Example 5;

[0066] Fig.11 is the carbon spectrum of the product obtained in Example 5;

[0067] Fig.12 is the hydrogen spectrum of the product obtained in Example 6;

[0068] Fig.13 This is the carbon spectrum of the product obtained in Example 6. DETAILED DESCRIPTION

[0069] The present invention is further described in detail below in conjunction with specific examples, but the embodiments of the present invention are not limited thereto.

[0070] ① Take a 500 mL three-necked flask, install a constant pressure dropping funnel, a reflux condenser and a glass stopper, add Mg (7.2 g, 296 mmol), add a stirrer, and add 16.8 mL of anhydrous Et2O under N2 protection. Then add a small amount of bromide (46.4 g, 296 mmol) in ether (89.7 mL). When successful initiation is observed, add the remaining bromide ether solution to the container within 80 minutes, keep reflux, and stir under reflux for 1 hour. Then cool to room temperature and add 62.6 mL of anhydrous Et2O to dilute. Then place the reaction bottle in an ice water bath and cool to 0 ° C, then add within 10 minutes. D -phenylglycine methyl ester hydrochloride (10g, 49.6 mmol), the reaction was heated to reflux for 3 h and the reaction solution was cooled to room temperature. The reaction solution was then carefully poured onto crushed ice, saturated NH4Cl solution, EA and water were added, the mixture was stirred for 1 h, separated in a large funnel, the aqueous phase was extracted three times with EA, the organic phase was washed with saturated brine, and finally dried with anhydrous Na2SO4, filtered, and concentrated in vacuo to obtain a yellow solid. The solid was dissolved in boiling MeOH, recrystallized at room temperature, and dried to obtain product A. A (10.5 mmol) and diethyl malonimide dihydrochloride (1.1556 g, 5 mmol) were added to DCM under N2 protection and refluxed for 18 h. After the reaction was completed, it was quenched with water, the aqueous layer was extracted three times with DCM, the mixed organic phase was washed with saturated brine, and dried over anhydrous Na2SO4. The residue after solvent evaporation was purified on silica gel to obtain C-5 substituted chiral bis-oxazoline ligand B. Subsequently, B (2 mmol) was added to a dried round-bottom flask, and dry THF (10 mL) was added under N2 atmosphere. The reaction solution was cooled to -78 °C and slowly added n BuLi (0.88 mL, 2.5 M, 2.2 mmol) was then added to the reaction solution. N,N,N',N' -Tetramethylethylenediamine (0.35 mL, 2.34 mmol). Stir at -78 °C for 1 h, then at 0 °C for 30 min. Subsequently, the reaction solution was cooled to -78 °C again, 4-toluenesulfonyl cyanide (405.9 mg, 2.24 mmol) was added, and the reaction was allowed to react at room temperature overnight. The reaction was quenched with saturated NH4Cl solution, stirred at room temperature for 5 min, extracted three times with Et2O, extracted three times with DCM, the organic phases were mixed, dried over anhydrous Na2SO4, and the residue after solvent evaporation was purified on silica gel to obtain chiral hemicorin compound C.

[0071] Example 1

[0072] The bromide was methyl bromide, which was separated and purified by column chromatography to obtain the target product. The column chromatography eluent used was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 10:1, and the yield was 53%. The structural characterization data of the product obtained in Example 1 are as follows (the nuclear magnetic spectrum is as follows Figure 1 (H-spectrum) and Figure 2 (Carbon-ion spectrum) shown):

[0073] Pale yellow solid (53% yield) was isolated by column chromatography(petroleum ether / ethyl acetate = 5:1). mp = 250 ℃. 1 H NMR (600 MHz, CDCl3) δ7.34 (dd, J = 7.9, 6.6 Hz, 4H), 7.29 (t, J = 7.3 Hz, 2H), 7.21 – 7.18 (m, 4H), 4.84 (s, 2H), 1.67 (s, 6H), 0.95 (s, 6H). 13 C NMR(151 MHz, CDCl3) δ 166.82,137.67, 128.47, 128.15, 126.71, 117.27, 89.16, 72.91, 50.83, 28.15,23.42.HRMS (APCI) m / z: Calcd for C 24 H 26 N3O2[M+H] + : 388.2020; found: 388.2012.[α] D 23 = -2.5 (c = 0.1, CHCl3)

[0074] Based on the above data, the structure of the obtained product is as follows:

[0075]

[0076] Example 2

[0077] The bromide was 4-fluorobromobenzene, which was separated and purified by column chromatography to obtain the target product. The column chromatography eluent used was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 10:1, and the yield was 89%. The structural characterization data of the product obtained in Example 2 are as follows (the nuclear magnetic spectrum is shown in Figure 3 (H-spectrum), Figure 4 (Carbon-spectrum) and Figure 5(Fluorine-spectrum) shown):

[0078] Pale yellow solid (89% yield) was isolated by column chromatography(petroleum ether / ethyl acetate = 5:1). mp = 286 ℃. 1 H NMR(600 MHz, CDCl3) δ7.68 – 7.64 (m, 4H), 7.17 – 7.14 (m, 4H), 7.12 – 7.08 (m, 6H), 6.92 – 6.88(m, 8H), 6.71 – 6.67 (m, 4H), 5.81 (s, 2H). 13 C NMR(151 MHz, CDCl3) δ 165.93,163.48, 162.57, 161.83, 160.93, 138.46, 138.44, 137.00, 134.50, 128.32,128.29, 128.27, 128.24, 128.17, 127.87, 116.26, 115.81, 115.66, 114.55,114.41, 94.70, 73.73, 63.14, 50.93, 29.68, 13.91. 19 F NMR(565 MHz, CDCl3) δ -112.74, -112.75, -112.76, -112.77, -112.77, -114.45, -114.46, -114.47, -114.48, -114.49.HRMS (APCI) m / z:Calcd for C 44 H 30 F4N3O2[M+H] + : 708.2269; found:708.2275. [α] D 23 = + 1.0 (c = 0.2, CH2Cl2).

[0079] Based on the above data, the structure of the obtained product is as follows:

[0080]

[0081] Example 3

[0082] The bromide was 4-methylbromobenzene, which was separated and purified by column chromatography to obtain the target product. The column chromatography eluent used was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 10:1, and the yield was 82%. The structural characterization data of the product obtained in Example 3 are as follows (NMR spectrum is shown in Figure 6 (H-spectrum) and Figure 7 (Carbon-ion spectrum) shown):

[0083] Pale yellow solid (82% yield) was isolated by column chromatography(petroleum ether / ethyl acetate = 5:1). mp = 170 ℃. 1 H NMR (600 MHz, CDCl3) δ7.58 (dd, J = 5.6, 2.3 Hz, 4H), 7.26 – 7.20 (m, 4H), 7.04 (d, J = 3.0 Hz, 6H),6.93 (d, J = 2.4 Hz, 4H), 6.83 (dd, J = 5.2, 2.9 Hz, 4H), 6.79 – 6.74 (m, 4H), 5.79 (d, J = 2.9 Hz, 2H), 2.36 (s, 6H), 2.10 (s, 6H). 13 C NMR (151 MHz, CDCl3) δ166.16, 140.29, 138.08, 137.64, 136.55, 136.04, 129.19, 128.01, 127.98,127.86, 127.74, 126.31, 126.04, 116.82, 95.30, 73.56, 50.63, 29.60, 21.01,20.78.HRMS (ESI) m / z:Calcd for C 48 H 42 N3O2[M+H] + : 692.3272; found: 692.3243.[α] D 23 = + 1.6 (c = 0.2, CH2Cl2).

[0084] Based on the above data, the structure of the obtained product is as follows:

[0085]

[0086] ②Step 1: Under nitrogen atmosphere, add anhydrous THF (30 mL) to a Schleck flask containing Mg (1.89 g, 78 mmol), and then add (CH2Br)2 (0.1 mL, 7.3 mmol). Add phenyl bromide (60 mmol) dropwise in THF (30 mL) and stir at room temperature. Then stir the mixture at 65 °C for 1 h. Under nitrogen conditions, dissolve diethyl oxalate (16.3 mL, 120 mmol) in THF (30 mL) in a round-bottom flask, cool to -78 °C, add the above Grignard reagent to the THF (30 mL) solution of diethyl oxalate within 10 min, stir at -78 °C for 1 h, then warm the reaction to room temperature and stir for another 20 min. After the reaction is completed, quench with saturated NaHCO3 solution, stir for 5 min, filter with diatomaceous earth, and wash with EA. The filtrate was extracted three times with EA, and the organic phase was washed with saturated brine, dried over anhydrous Na2SO4, concentrated, and purified on silica gel to obtain product D.

[0087] Step 2: Under nitrogen protection, D (39 mmol) and ( R )-tert-Butylsulfenamide (4.73 g, 39 mmol) was dissolved in anhydrous THF (60 mL) and Ti(O i Pr)4 (17.3 mL, 58.5 mmol). After stirring at 65 °C overnight, the solution was cooled to room temperature, diluted with EA, quenched with 10% aqueous NaOH solution, stirred for 10 min, and then filtered with EA. The filtrate was washed with saturated brine and dried over anhydrous Na2SO4. The residue after solvent evaporation was purified by silica gel to obtain the product E of step 2.

[0088] Step 3: Under nitrogen atmosphere, E (17.53 mmol) was dissolved in dry THF (50 mL), cooled to -78 °C, stirred for 5 min, and then tri-sec-butyl borohydride lithium (19.3 mL, 1.0 M, 19.3 mmol) was slowly added and stirred at -78 °C for 5 h. Then, the mixture was quenched with saturated NH4Cl solution at -78 °C, stirred to room temperature, and then the mixture was transferred to a separatory funnel containing saturated brine and EA, extracted three times with EA, and the organic phase was washed with saturated brine, dried over anhydrous Na2SO4, concentrated, and purified on silica gel to obtain the product F of step 3.

[0089] Step 4: F (17 mmol) was dissolved in MeOH (40 mL), and HCl / dioxane (17 mL, 4.0 M, 68 mmol) was slowly added at 0 °C and reacted at room temperature for 30 min. The solvent was then concentrated and washed with ether to obtain a white solid 3,5-disubstituted phenylaminoacetate G.

[0090] Step 5: Take a three-necked flask, install a constant pressure dropping funnel, a reflux condenser and a glass stopper, add Mg (1.458 g, 60 mmol), add a stirrer, and add anhydrous Et2O under N2 protection. Then add a small amount of bromobenzene (9.42 g, 60 mmol) solution dissolved in ether. At the beginning of the reaction, add the remaining bromobenzene solution to the container within 80 min, keep reflux, stir the mixed solution under reflux for another 1 h, cool to room temperature, and add anhydrous Et2O to dilute. The reaction bottle is cooled in an ice-water bath, and then 3,5-disubstituted phenylaminoacetate G (10 mmol) is added within 10 min. After the reaction is heated to reflux for 3 h, the reaction bottle is condensed in an ice-water bath. The reaction solution was then carefully poured onto crushed ice; saturated NH4Cl solution, EA and water were added, the mixture was stirred for 1 h, separated in a large funnel, the aqueous phase was extracted three times with EA, the organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified on silica gel to obtain amino acid ester hydrochloride H.

[0091] Step 6: H (10.5 mmol) and diethyl malonimide dihydrochloride (1.1556 g, 5 mmol) were added to DCM under N2 protection and refluxed for 18 h. After the reaction was completed, the reaction was quenched with water, and the aqueous layer was extracted three times with DCM. The mixed organic phase was washed with saturated brine and dried over anhydrous Na2SO4. The residue after solvent evaporation was purified by silica gel to obtain C-4 substituted chiral bisoxazoline ligand I.

[0092] Step 7: Add the prepared C-4 (3,5-disubstituted phenyl) substituted chiral bis-oxazoline ligand I (2 mmol) to a dried round-bottom flask, add dry THF (10 mL) under N2 atmosphere, cool the reaction solution to -78 °C, and slowly add n BuLi (0.88 mL, 2.5 M, 2.2 mmol) was then added to the reaction solution. N,N,N',N'-Tetramethylethylenediamine (0.35 mL, 2.34 mmol). Stir at -78 °C for 1 h, then at 0 °C for 30 min. Subsequently, the reaction solution was cooled to -78 °C again, 4-toluenesulfonyl cyanide (405.9 mg, 2.24 mmol) was added, and the reaction was allowed to react at room temperature overnight. The reaction was quenched with saturated NH4Cl solution, stirred at room temperature for 5 min, extracted three times with Et2O, extracted three times with DCM, the organic phases were mixed, dried over anhydrous Na2SO4, and the residue after solvent evaporation was purified on silica gel to obtain hemicorin compound J

[0093] Example 4

[0094] The phenyl bromide is 3,5-bis(trifluoromethyl)bromobenzene, which is separated and purified by column chromatography to obtain the target product. The column chromatography eluent used is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 5:1, and the yield is 54%. The structural characterization data of the product obtained in Example 4 are as follows (the nuclear magnetic spectrum is as follows Figure 8 (H-spectrum) and Fig. 9 (Carbon-ion spectrum) shown):

[0095] Whitesolid (54% yield) was isolated by column chromatography(petroleum ether / ethyl acetate = 5:1). mp = 272 ℃. 1 H NMR (600 MHz, CDCl3) δ7.71 (d, J = 7.5 Hz, 4H), 7.43 (t, J = 7.7 Hz, 4H), 7.36 (t, J = 7.3 Hz, 2H), 7.08(s, 2H), 6.96 (dt, J = 7.1, 3.5 Hz, 10H), 6.69 (d, J = 1.5 Hz, 4H), 5.78 (s, 2H), 1.10 (s, 36H). 13 C NMR(151 MHz, CDCl3) δ 166.23, 150.36, 143.22, 139.03,136.33, 128.58, 128.31, 127.34, 126.93, 126.52, 126.31, 122.45, 121.69,95.25, 74.42, 50.60, 34.56, 31.17.HRMS (ESI) m / z:Calcd for C60 H 66 N3O2[M+H] + :860.5150; found: 860.5153. [α] D 23 = + 0.3 (c = 0.1, CH2Cl2).

[0096] Based on the above data, the structure of the obtained product is as follows:

[0097]

[0098] Example 5

[0099] The phenyl bromide is 3,5-bisphenyl bromobenzene, which is separated and purified by column chromatography to obtain the target product. The column chromatography eluent used is a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 5:1, and the yield is 50%. The structural characterization data of the product obtained in Example 5 are as follows (the nuclear magnetic spectrum is as follows Fig.10 (H-spectrum) and Fig.11 (Carbon-ion spectrum) shown):

[0100] Whitesolid (50% yield) was isolated by column chromatography(petroleum ether / ethyl acetate = 5:1). mp = 187 ℃. 1 H NMR (600 MHz, CDCl3) δ7.73 (d, J = 7.5 Hz, 4H), 7.48 (d, J = 1.3 Hz, 2H), 7.43 – 7.41 (m, 3H), 7.38 (d, J = 6.8 Hz, 8H), 7.36 – 7.32 (m, 13H), 7.23 (s, 1H), 7.08 (d, J = 4.4 Hz, 13H),7.04 (d, J = 4.1 Hz, 2H), 5.99 (s, 2H). 13 C NMR(151 MHz, CDCl3) δ 166.29, 142.82,141.55, 140.61, 139.08, 138.42, 128.72, 128.47, 127.79 – 127.33, 127.16,126.61, 126.27 (d, J= 10.9 Hz), 125.99, 116.65, 95.33, 74.01, 50.85.HRMS (ESI)m / z:Calcd for C 68 H 50 N3O2[M+H] + : 940.3898; found: 940.3899. [α] D 23 = - 0.1 (c =0.3, CH2Cl2).

[0101] Based on the above data, the structure of the obtained product is as follows:

[0102]

[0103] Example 6

[0104] The phenyl bromide is 3,5-di-tert-butyl-4-methoxybromobenzene, which is separated and purified by column chromatography to obtain the target product. The column chromatography eluent used is a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 5:1. The yield is 62%. The structural characterization data of the product obtained in Example 6 are as follows (the nuclear magnetic spectrum is as follows Fig.12 (H-spectrum) and Fig.13 (Carbon-ion spectrum) shown):

[0105] Pale yellow solid (62% yield) was isolated by column chromatography(petroleum ether / ethyl acetate = 5:1). mp = 256 ℃. 1 H NMR (600 MHz, CDCl3) δ7.69 (dd, J = 14.1, 10.9 Hz, 4H), 7.49 – 7.35 (m, 6H), 7.01 – 6.91 (m, 10H), 6.75 (dd, J = 28.4, 3.6 Hz, 4H), 5.76 (d, J = 3.7 Hz, 2H), 3.47 (dd, J = 9.6, 2.9Hz, 6H), 1.21 (d, J = 3.4 Hz, 36H). 13 C NMR(151 MHz, CDCl3) δ 166.26, 159.27,142.95 (d, J= 13.2 Hz), 139.05, 130.99, 128.56, 128.30 (d, J = 13.2 Hz), 127.27(d, J = 5.0 Hz), 126.86 (d, J = 10.9 Hz), 126.69 – 126.09 (m), 126.09 – 125.82(m), 116.86 (d, J = 15.2 Hz), 95.27, 95.05, 73.81, 64.24 (d, J = 4.7 Hz), 50.53,35.42, 31.71.HRMS (ESI) m / z:Calcd for C 62 H 70 N3O2[M+H] + : 920.5361; found:920.5358. [α] D 23 = + 0.2 (c = 0.2, CH2Cl2).

[0106] Based on the above data, the structure of the obtained product is as follows:

[0107]

Claims

1. A method for synthesizing a C-5 substituted chiral hemicorin compound having a structure represented by general formula (I), characterized in that: The structure shown in general formula (I) is: ； The R 1 is methyl, 4-fluorophenyl, 4-methylphenyl or 1-naphthyl; the Ph is phenyl; The synthesis method of the C-5 substituted chiral hemicorin compound having the structure shown in the general formula (I) is as follows: first, in an inert gas atmosphere, organic magnesium bromide and D -phenylglycine methyl ester hydrochloride was refluxed in ether and subsequently treated to obtain (R) -2-amino-1,1-disubstituted-2-phenyl-1-ol A; then, A and diethyl malonimide dihydrochloride were refluxed in dichloromethane, and the C-5 substituted chiral bisoxazoline compound B was obtained after subsequent treatment; finally, B and 4-toluenesulfonyl cyanide were reacted in the presence of n-butyl lithium, N,N,N',N' - reacting under the action of tetramethylethylenediamine and tetrahydrofuran, and obtaining a chiral hemicorin compound C after treatment; The organic magnesium bromide and D The molar ratio of A to diethyl malonimide dihydrochloride is 2.1:1; the molar ratio of B to 4-toluenesulfonyl cyanide is 1:1.12; the molar ratio of B to n-butyl lithium is 1:1.1; the molar ratio of B .... N,N,N',N' -tetramethylethylenediamine is 1:1.17; the subsequent treatment refers to cooling, concentrating and purifying the product after the reaction; the eluent of the column chromatography is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is (5-100):1; the reaction equation is: 。 2. A method for synthesizing a C-4 substituted chiral hemicorin compound having a structure represented by general formula (II), characterized in that: The structure shown in general formula (II) is: ； The R 2 is 3,5-di-tert-butyl, 3,5-diphenyl, 3,5-bistrifluoromethyl or 3,5-di-tert-butyl-4-methoxy; wherein Ph is phenyl; The synthesis method of the C-4 substituted chiral hemicorin compound having the structure shown in general formula (II) is: Step 1: Bromide and magnesium turnings are reacted in tetrahydrofuran with 1,2-dibromoethane to generate a Grignard reagent, which then reacts with diethyl oxalate to obtain product D; Step 2: D and ( R) - tert-butylsulfenamide reacts with tetraisopropyl titanate to obtain product E in tetrahydrofuran solution; Step 3: At -78 °C, lithium tri-sec-butylborohydride is used in tetrahydrofuran to reduce the carbon-nitrogen double bond of E to obtain product F; Step 4: Add hydrogen chloride / dioxane to the methanol solution of F to obtain product G; Step 5: G is reacted with phenylmagnesium bromide in ether under reflux to obtain amino acid ester hydrochloride H; Step 6: reflux H and diethyl malonimide dihydrochloride in dichloromethane, and obtain C-4 substituted chiral bis-oxazoline compound I after subsequent treatment; Step 7: I and 4-toluenesulfonyl cyanide in n-butyl lithium, N,N,N',N' - reacting under the action of tetramethylethylenediamine and tetrahydrofuran, and obtaining a chiral hemicorin compound J after treatment; The molar ratio of the bromide to magnesium and 1,2-dibromoethane in step 1 is 1:1.3:0.12; the molar ratio of bromide to diethyl oxalate is 1:2; the molar ratio of D to ( R) -tert-butylsulfenamide has a molar ratio of 1:1; D has a molar ratio of tetraisopropyl titanate of 1:1.5; the molar ratio of E in step 3 to lithium tri-sec-butylborohydride is 1:1.1; the molar ratio of F in step 4 to hydrogen chloride / dioxane is 1:4; the molar ratio of G in step 5 to phenylmagnesium bromide is 1:6; the molar ratio of H in step 6 to diethyl malonimide dihydrochloride is 2.1:1; the molar ratio of I in step 7 to 4-toluenesulfonyl cyanide is 1:1.12; the molar ratio of I to n-butyl lithium is 1:1.1; the molar ratio of I to N,N,N',N' -tetramethylethylenediamine has a molar ratio of 1:1.17; the subsequent treatment refers to cooling, concentrating and purifying the product after the reaction; the eluent of the column chromatography is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is (5-100):1; The reaction equation is: 。

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