Two chiral spiral dihydrophenalene structures and asymmetric synthesis method thereof

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to two chiral spiral dihydrophenalene structures and an asymmetric synthesis method thereof. The invention relates to two chiral spiral dihydrophenalene structures and derivative compounds thereof, which are characterized by being a compound or an enantiomer or a racemate of the following A and a compound or an enantiomer or a racemate of the following B, the invention relates to a compound with a brand new structure, enantioselective synthesis of two chiral helicodihydrophenalene structure derivatives is realized through an asymmetric synthesis method catalyzed by chiral rhodium for the first time, and the method has the advantages of high yield and good enantioselectivity (ee value gt; and the method has the advantages of high industrial production value and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to two chiral spirodihydrophene structures and an asymmetric synthesis method thereof. Background Art

[0002] Asymmetric catalytic synthesis is a frontier field of organic synthesis, playing a vital role in drug development, preparation of chiral chemicals and synthesis of chiral materials. Among them, the design and development of new chiral catalysts and chiral ligands are the core of asymmetric catalytic research. The introduction of spirocyclic structures has greatly enriched the diversity of chiral catalysts and chiral ligands, and has been successfully applied to asymmetric transformation reactions such as asymmetric catalytic hydrogenation, asymmetric carbon-carbon bond formation or carbon-heterobond formation, and synthesized many valuable chiral products. However, the inherent rigidity of the spirocyclic structure also limits the scope of application of the corresponding chiral catalyst, and the development of structurally diverse spirocyclic structures is the key to solving this problem. Spirodihydrophenanthene is an important new type of spirocyclic structure. The literature (J.Am.Chem.Soc.2021,143,12445) reports an asymmetric synthesis method (E) of chiral spirodihydrophenanthene structures, and the chiral catalysts and chiral ligands derived from them show excellent reactivity and chiral induction ability. However, the development of new spirodihydrophenanthene structures is still very limited.

[0003]

[0004] The present invention develops two novel spirodihydroquinone structures containing different aromatic substituents at the 3,3, positions, and develops an asymmetric synthesis method and an asymmetric catalytic synthesis application thereof. Summary of the invention

[0005] Purpose of the Invention

[0006] The invention provides two chiral spirodihydrophene structures and asymmetric synthesis methods and applications thereof.

[0007] Technical Solution

[0008] In order to achieve the above technical objectives, the present invention adopts the following technical solutions:

[0009] Two chiral spirodihydroquinone structures and derivative compounds thereof, characterized in that they are the following compounds A, enantiomers or racemates, and compounds B, enantiomers or racemates

[0010]

[0011] Wherein Ar is phenyl, 4-methylphenyl, 4-fluorophenyl, 4-bromophenyl, 3-methylphenyl, 3-bromophenyl, 3-chlorophenyl, 3.5-di-tert-butylphenyl

[0012] A method for asymmetric synthesis of two chiral spirodihydrophene structures and derivative compounds thereof, characterized in that:

[0013]

[0014] The following steps are involved:

[0015] Step (1): Acetone undergoes a condensation reaction with different aromatic substituted aldehydes under alkaline conditions to generate I;

[0016] Step (2): Under the catalysis of a chiral rhodium catalyst, compound I and arylboron reagent II undergo an asymmetric addition reaction to generate intermediate III, which is separated and purified; when boron trifluoride etherate and potassium phosphate are added, intermediate III undergoes an intramolecular Friedel-Crafts reaction to prepare compound IV; boron trifluoride etherate and trifluoroacetic acid are added to generate compound V; a mixture of compound IV and V is obtained by adding only boron trifluoride etherate;

[0017] in:

[0018] In step (1), the reaction solvent is selected from an aqueous solution of an inorganic base, which is one or more of potassium carbonate, cesium carbonate, tripotassium phosphate, lithium hydroxide, sodium hydroxide and potassium hydroxide, preferably potassium hydroxide; preferably, the amount of the inorganic base added is 2 equivalents of different aromatic substituted aldehydes; wherein the molar ratio of different aromatic substituted aldehydes to acetone is 2 to 5:1, preferably 2:1; the reaction temperature is 0 to 50°C, preferably 15 to 25°C; and the reaction time is 6 to 12 hours, preferably 8 to 12 hours.

[0019] Further, compound I has the following structure:

[0020]

[0021] In step (2):

[0022] The chiral rhodium catalyst has a general structural formula of [RhCl(L)x]2 (x=1 / 2), wherein the chiral ligand L is selected from a chiral diene ligand, a chiral heteroatom ligand, a chiral heteroatom olefin ligand, etc.;

[0023] Further, the chiral ligand is selected from the following structures:

[0024]

[0025]

[0026] Furthermore, the chiral ligand is L: Ar = 2-naphthy.

[0027] Step (2) The reaction solvent is selected from one or more of tetrahydrofuran, ethanol, toluene and water, preferably a mixed solvent of ethanol and water; preferably, 0.5 to 2 mL of the reaction solvent is added to 0.1 mmol of compound I, more preferably 1 to 1.5 mL;

[0028] The molar ratio of compound I, aryl boron reagent II and chiral rhodium catalyst is 1:1-5:0.005-0.05, the reaction temperature for converting compound I into aryl boron reagent II is 40-100°C, and the reaction time is 10-16h.

[0029] When compound III is converted to compound IV in step (2), 5-10 molar equivalents of boron trifluoride etherate and 1-2 molar equivalents of potassium phosphate are added.

[0030] When compound III is converted to compound V in step (2), the added boron trifluoride etherate is 5-10 molar equivalents and the added trifluoroacetic acid is 4-5 molar equivalents.

[0031] Beneficial Effects

[0032] 1. The present invention generates compounds IV and V with completely new structures, which have not been reported in the literature and are completely new compounds. The inventors further found that according to the prior art (J.Am.Chem.Soc.2021,143,12445), the presence of an aromatic substituent at the 3,3, position, i.e., the presence of steric hindrance, makes it difficult to form the compounds described in the present invention according to the method;

[0033] Drawing on the article published by the applicant (https: / / doi.org / 10.1002 / anie.201812266) and the patent application CN 109400445A, which discloses an asymmetric synthesis method of 3,3'-diaryl-substituted chiral spirocyclic diphenol compounds, the inventor creatively uses the same chiral rhodium catalyst for the present invention. It should be noted that the difference between the two is that the present invention contains a naphthalene structure, while the patent discloses a phenol structure, that is, the present invention is a spirodihydrophenanthene structure, while the patent discloses a spirocyclic diphenol structure, which belong to different types of compounds. Further, in Example 2, a chiral rhodium catalyst is used to produce intermediate III; further, the inventor surprisingly found that when adding boron trifluoride etherate and potassium phosphate, intermediate III undergoes an intramolecular Friedel-Crafts reaction to prepare compound IV; adding boron trifluoride etherate and trifluoroacetic acid to generate compound V; adding only boron trifluoride etherate or adding boron trifluoride etherate and other bases to obtain a mixture of compounds IV and V, that is, the inventor discovered a method for directional generation of IV or V.

[0034] 2. The present invention relates to compounds of a completely new structure, and for the first time realizes the enantioselective synthesis of two chiral spirodihydroquinone derivatives through an asymmetric synthesis method catalyzed by chiral rhodium. This method has the advantages of high yield and good enantioselectivity (ee value>99%), and has high industrial production value. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 is the racemic liquid phase spectrum of IV-a;

[0036] Figure 2 This is the chiral liquid phase spectrum of IV-a;

[0037] Figure 3 is the racemic liquid phase spectrum of Va;

[0038] Figure 4 This is the chiral liquid phase spectrum of Va. DETAILED DESCRIPTION

[0039] The present invention is further described below using specific examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions shall be selected according to conventional methods and conditions, or according to the product instructions.

[0040] [Rh(COD)Cl]2 was purchased from Sane Chemical Technology (Shanghai) Co., Ltd. All air-sensitive operations were performed using Schlenk technology. Silica gel column chromatography used Shandong Yantai silica gel plates (HSGF 254), TLC color development used UV light (254nm) or KMnO4, NMR was characterized using a Bruker AVANCE-300 or 500 nuclear magnetic resonance instrument, the solvent was CDCl3 or DMSO-d6, the chemical shift was expressed as δ, the unit was ppm, and the unit of the coupling constant was Hz. 1 In H NMR, s represents a singlet, d represents a doublet, t represents a triplet, q represents a quartet, m represents a multiplet, br represents a broad peak, and t represents a R (major) indicates the main product peak time, t R (minor) indicates the peak time of the by-product, and the by-product is generally a diastereoisomer of the main product. The enantiomeric excess is determined using SHIMADZU SPD-20A, and the chiral column is a Dacel IB column or IF column.

[0041] Example 1

[0042]

[0043] 1 mmol (1 equiv) of aromatic aldehydes with different substitutions and acetone (0.5 equiv) were weighed into a reaction bottle, methanol / water = 1:1 was added, 6N NaOH (2 mL) solution was slowly added dropwise at 0°C, and the reaction was carried out at room temperature for 4 h. After the reaction was completed, 1 M HCl was used to neutralize the mixture, and the mixture was extracted with ethyl acetate, dried, concentrated, and column chromatography was performed to obtain a light yellow solid I.

[0044] Using the following reaction route, taking the preparation of compound Ia as an example, the general preparation method of II described in the present invention is described in detail in this example:

[0045]

[0046] Under nitrogen protection, VI (500 mg, 2.24 mmol) was put into a reaction bottle, THF (5 mL) was added and stirred, the temperature was lowered to -78 ° C, n-BuLi (2.7 mL, 6.73 mmol, 3 equiv.) was added and reacted for 0.5 h, B (i-OPr) 3 (2.1 g, 11.21 mmol) was added, and the temperature was raised to room temperature for reaction for 12 h. After the reaction was completed, the reaction solution was dropped into 3M hydrochloric acid solution and stirred for 3 h, extracted with ethyl acetate three times, washed once with saturated brine, dried, concentrated, and column chromatography (dichloromethane / methanol = 20 / 1, v / v) was used to obtain VII168 mg of a white solid with a yield of 40%

[0047] Spectral data:

[0048] 1 H NMR (300MHz, DMSO-d6): δ9.60(s,1H),8.24(s,2H),7.80–7.65(m,3H),7.61(d d,J=6.8,1.4Hz,1H),7.22(dd,J=8.1,6.8Hz,1H),7.03(dd,J=8.8,2.5Hz,1H). 13 C NMR(101MHz, DMSO-d6): δ155.1,137.3,132.3,129.6,129.0,127.5,121.8,117.9,110.3.HRMS(ESI+):calcd.for C 10 H9 10 BO3 + [M+H] + 188.0754,found 188.0754.calcd.for C 10 H9 11 BO3 + [M+H] + 189.0718, found 188.0723.

[0049] Example 2

[0050]

[0051] Under the protection of high-purity nitrogen, compound Ia (23.4 mg, 0.1 mmol), 7-hydroxynaphthalene boronic acid (56.4 mg, 0.3 mmol), [RhCl (L)] 2 (1.9 mg, 2 mol%), potassium hydroxide aqueous solution (0.1 mL, 0.05 M, 5 mol%) and anhydrous ethanol (1 mL) were added to the Schlenk tube in sequence. After the addition, the mixture was reacted at 60°C for 12 h under the protection of nitrogen. After cooling to room temperature, water (5 mL) and ethyl acetate (5 mL) were added to the Schlenk tube for extraction, the organic layer was taken out, the aqueous layer was extracted once with ethyl acetate (5 mL), the solvent was evaporated to obtain a crude product, and the intermediate III-a was obtained by column chromatography purification (PE: EA = 4: 1, v / v), as a white solid of 50.6 mg, with a yield of 97%, a dr value> 20: 1, and an ee value> 99%.

[0052] Spectral data:

[0053] [α] D 25 +15(c 0.15,CHCl3); 1 H NMR (300MHz, CDCl3): δ7.72(d,J=8.8Hz,2H),7.63(d,J=8.1Hz,2H),7.49(d,J= 2.4Hz, 2H), 7.23–6.95 (m, 18H), 5.20 (dd, J=8.3, 6.1Hz, 2H), 3.27–3.00 (m, 4H). 13 C NMR (101MHz, CDCl3): δ210.4,154.1,142.9,137.9,132.5,130.9,129.4,128.5,127.8 ,127.1,126.4,125.0,122.9,117.7,105.7,49.9,41.0,29.8.HRMS(ESI+):calcd.for C 37 H 30 O3 + [M+H] + 523.2268, found 523.2269.

[0054] HPLC analysis: CHIRALPAK IB column, n-Hexane / i-PrOH=95:5, flow rate 1.0mL / min, uv-vis detection atλ=210nm,t major =14.87min,tminor =22.27min (major diastereomer)

[0055] Example 3

[0056]

[0057] Under the protection of high-purity nitrogen, compound Ia (23.4 mg, 0.1 mmol), 7-hydroxynaphthaleneboric acid (56.4 mg, 0.3 mmol), [RhCl(L)]2 (1.9 mg, 2 mol%), potassium hydroxide aqueous solution (0.1 mL, 0.05 M, 5 mol%) and anhydrous ethanol (1 mL) were added to a Schlenk tube in sequence. After the addition was completed, the mixture was reacted at 60 °C for 12 h under the protection of nitrogen. Cool to room temperature, add water (5mL) and ethyl acetate (5mL) to the Schlenk tube for extraction, take out the organic layer, extract the water layer with ethyl acetate (5mL) once more, evaporate the solvent to obtain a crude product, and purify it by column chromatography (PE:EA=4:1, v / v) to obtain intermediate III-a. Add III-a (52.2mg, 0.1mmol) and potassium phosphate (21.2mg, 0.1mmol) to the Schlenk, add anhydrous acetonitrile (1.0mL), slowly drop boron trifluoride ether solution (62μL, 0.5mmol) to the reaction bottle, move to 60℃, and react for 12h. Add water (2mL) to quench, extract with ethyl acetate (3mL×3), and remove the solvent under reduced pressure to obtain crude III-a. 48.8mg of white solid (PE:EA=4:1, yield 97%, dr value>20:1, ee value>99% was obtained by column chromatography.

[0058] Spectral data:

[0059] [α] D 25 -381(c 0.11,CHCl3); 1 H NMR (300MHz, CDCl3): δ7.80(d,J=8.9Hz,2H),7.69(d,J=8.1Hz,2H),7.44–7.18(m,12H),7.12(d,J =8.8Hz,2H),6.95(d,J=7.2Hz,2H),5.41(s,2H),4.55(dd,J=12.3,5.5Hz,2H),2.77–2.59(m,4H). 13C NMR (101MHz, CDCl3): δ152.1,144.6,136.9,130.7,130.3,130.2,129.0,127.4 ,127.1,126.8,123.6,118.9,118.0,42.5,40.4,40.2.HRMS(ESI+):calcd.for C 37 H 28 O2 + [M+H] + 505.2162, found 505.2165.

[0060] HPLC analysis: CHIRALPAK IB column, n-Hexane / i-PrOH=97:3, flow rate 1.0mL / min, uv-vis detection atλ=210nm,t major =13.30min,t minor =11.63min (major diastereomer).

[0061] Implementation 4

[0062] According to the preparation method of Example 3, only the biarylphenyl ketone with different reaction structures was changed to prepare the chiral spirodihydrophenanthrene derivatives shown below:

[0063]

[0064] The yield and structural identification data of the compound shown in formula III-b:

[0065] White solid, yield 91%, dr value>20:1, ee value>99%, specific rotation: [α] D 25 -351(c 0.12,CHCl3); 1 H NMR (300MHz, CDCl3): δ7.83(d,J=8.9Hz,2H),7.72(dt,J=8.2,1.2Hz,2H),7.34–7.19(m,10H),7.15(d,J=8.9H z,2H),7.01(dt,J=7.2,1.5Hz,2H),5.45(s,2H),4.55(dd,J=12.0,5.6Hz,2H),2.81–2.55(m,4H),2.41(s,2H); 13C NMR (75MHz, CDCl3): δ152.1,141.5,137.2,136.6,130.7,130.3,130.2,129.6,12 7.3,126.7,123.6,118.9,118.1,42.0,40.4,40.2,21.2.HRMS(ESI+):calcd.for C 37 H 26 F2O2 + [M+H] + 533.2475, found 533.2493.

[0066] HPLC conditions: CHIRALPAK IB column, n-Hexane / i-PrOH=97:3, flow rate 1.0mL / min, uv-vis detection atλ=210nm, t major =10.99min,t minor =9.58min (major diastereomer).

[0067] The yield and structural identification data of the compound shown in formula III-c:

[0068] White solid, yield 85%, dr value>20:1, ee value>99%, specific rotation: [α] D 25 -282 (c 0.17, CHCl3); 1 H NMR (400MHz, CDCl3): δ7.83(d,J=8.9Hz,2H),7.73(d,J=8.1Hz,2H),7.40–7.32(m,4H),7.31–7.23(m,2H) ,7.17–7.05(m,6H),6.95(d,J=7.2Hz,2H),5.39(s,2H),4.56(dd,J=12.7,5.0Hz,2H),2.83–2.46(m,4H); 13 C NMR (75MHz, CDCl3): δ162.0 (J=243.7Hz), 152.1, 140.2 (J=3.7Hz), 136.7, 130.8, 130.3, 130.1, 127.5,126.7,123.6,119.0,118.0,115.8(J=20.5Hz),41.8,40.3,40.2.HRMS(ESI+):calcd.for C 37 H 26 F2O2 + [M+H] +541.1973, found 541.1968.

[0069] HPLC conditions: CHIRALPAK IF column, n-Hexane / i-PrOH=95:5, flow rate 1.0mL / min, uv-vis detection atλ=210nm, t major =10.86min,t minor =8.69min (major diastereomer).

[0070] The yield and structural identification data of the compound shown in formula III-d:

[0071] White solid, yield 87%, dr value>20:1, ee value>99%, specific rotation: [α] D 25 -408 (c 0.14, CHCl3); 1 H NMR (400MHz, DMSO-d6): δ8.87(s,2H),7.58(dd,J=12.6,6.0Hz,8H),7.34(d,J=8.1Hz,4H),7.06(t,J=7.6Hz,2H),6. 99(d,J=8.7Hz,2H),6.56(d,J=7.1Hz,2H),4.58–4.43(m,2H),2.85(t,J=13.4Hz,2H),2.44(dd,J=13.2,3.9Hz,2H); 13 C NMR (101MHz, DMSO-d6): δ150.6,144.8,136.9,131.5,130.9,128.3,126.5,124.9,123.9,121.3,119.4,118.5,41.2,40.3,38.6.HRMS(ESI+):calcd.for C 37 H 26 79 Br2O2 + [M+H] + 661.0372,found661.0396.calcd.for C 37 H 26 81 Br2O2 + [M+H] + 665.0332, found 665.0327.

[0072] HPLC conditions: CHIRALPAK IB column, n-Hexane / i-PrOH=97:3, flow rate 1.0mL / min, uv-vis detection atλ=210nm, t major =27.03min,t minor =17.87min (major diastereomer).

[0073] The yield and structural identification data of the compound shown in formula III-e:

[0074] White solid, yield 86%, dr value>20:1, ee value>99%, specific rotation: [α] D 25 -299 (c 0.18, CHCl3); 1 H NMR (400MHz, CDCl3): δ7.82(d,J=8.9Hz,2H),7.71(d,J=8.1Hz,2H),7.37–7.05(m,12H),6.99(dt ,J=7.2,1.5Hz,2H),5.43(s,2H),4.53(dd,J=12.5,5.3Hz,2H),δ2.82–2.54(m,4H).,2.38(s,2H); 13 C NMR (75MHz, CDCl3): δ152.1, 144.5, 138.5, 137.1, 130.7, 130.2 (d, J = 5.8Hz), 128.8, 12 7.8,127.3,126.9,123.6,118.9,118.1,42.4,40.4,40.1,21.6.HRMS(ESI+):calcd.for C 39 H 32 O2 + [M+H] + 533.2475, found 533.2478.

[0075] HPLC conditions: CHIRALPAK IF column, n-Hexane / i-PrOH=97:3, flow rate 1.0mL / min, uv-vis detection atλ=210nm, t major =26.57min,t minor =9.06min (major diastereomer).

[0076] The yield and structural identification data of the compound shown in formula III-f:

[0077] White solid, yield 83%, dr value>20:1, ee value>99%, specific rotation: [α] D 25 -321(c 0.16,CHCl3); 1 H NMR (400MHz, CDCl3): δ7.84(d,J=8.9Hz,2H),7.74(d,J=8.1Hz,2H),7.55(s,2H),7.46(dt,J=7.8,1.6Hz,2H),7.38–7.23 (m,6H),7.15(d,J=8.9Hz,2H),6.96(dd,J=7.2,1.7Hz,2H),5.39(s,2H),4.53(dd,J=12.0,5.8Hz,2H),2.75–2.60(m,4H); 13 C NMR (75MHz, CDCl3): δ152.1,146.9,136.0,130.8,130.6,130.3,130.0,127.7,126.9,123.7,119.0,117.8,42.3,40.3,39.9.HRMS(ESI+):calcd.for C 37 H 26 79 Br2O2 + [M+H] + 661.0372,found 661.0360.calcd.for C 37 H 26 81 Br2O2 + [M+H] + 665.0332, found 665.0327.

[0078] HPLC conditions: CHIRALPAK IF column, n-Hexane / i-PrOH=97:3, flow rate 1.0mL / min, uv-vis detection atλ=210nm, t major =15.20min,t minor =12.99min (major diastereomer).

[0079] The yield and structural identification data of the compound shown in formula III-g:

[0080] White solid, yield 79%, dr value>20:1, ee value>99%, specific rotation: [α] D 25 -313 (c 0.12, CHCl3); 1H NMR (300MHz, CDCl3): δ7.86(d,J=8.9Hz,2H),7.77(d,J=8.1Hz,2H),7.45(s,2H),7.40–7.25(m,8H),7.16( d,J=8.9Hz,2H),7.00(dt,J=7.3,1.4Hz,2H),5.49(s,2H),4.58(dd,J=10.5,7.1Hz,2H),2.84–2.62(m,4H); 13 C NMR (75MHz, CDCl3): δ152.1,146.6,136.0,134.7,130.8,130.3,130.3,130.0,12 7.7,127.4,126.9,123.7,119.0,117.8,42.3,40.3,39.9.HRMS(ESI+):calcd.for C 37 H 26 35 Cl2O2 + [M+H] + 573.1383,found573.1388.calcd.for C 37 H 26 37 Cl2O2 + [M+H] + 577.1324, found 577.1342.

[0081] HPLC conditions: CHIRALPAK IB column, n-Hexane / i-PrOH=97:3, flow rate 1.0mL / min, uv-vis detection atλ=210nm, t major =19.10min,t minor =11.57min (major diastereomer).

[0082] The yield and structural identification data of the compound shown in formula III-h:

[0083] White solid, yield 64%, dr value>20:1, ee value>99%, specific rotation: [α] D 25 -207(c 0.12,CHCl3); 1H NMR (300MHz, CDCl3): δ7.85(d,J=8.9Hz,2H),7.73(d,J=8.1Hz,2H),7.40(d,J=1.9Hz,2H),7.35–7.11( m,10H),7.07–6.98(m,2H),5.46(s,2H),4.61(dd,J=13.0,4.1Hz,2H),2.87–2.64(m,4H),1.37(s,36H); 13 C NMR (75MHz, CDCl3): δ152.0,143.0,137.4,130.6,130.3,130.2,127.0,126.2,1 23.5,120.9,118.7,118.0,43.2,40.7,40.1,34.9,31.6.HRMS(ESI+):calcd.for C 53 H 60 O2 + [M+H] + 729.4666, found 729.4655.

[0084] HPLC conditions: CHIRALPAK IF column, n-Hexane / i-PrOH=99.7:0.3, flow rate 1.0mL / min, uv-vis detection atλ=210nm, t major =10.40min,t minor =11.72min (major diastereomer).

[0085] Example 5

[0086]

[0087] Under the protection of high-purity nitrogen, compound Ia (23.4 mg, 0.1 mmol), 7-hydroxynaphthaleneboric acid (56.4 mg, 0.3 mmol), [RhCl(L)]2 (1.9 mg, 2 mol%), potassium hydroxide aqueous solution (0.1 mL, 0.05 M, 5 mol%) and anhydrous ethanol (1 mL) were added to a Schlenk tube in sequence. After the addition was completed, the mixture was reacted at 60 °C for 12 h under the protection of nitrogen. Cool to room temperature, add water (5mL) and ethyl acetate (5mL) to the Schlenk tube for extraction, take out the organic layer, extract the water layer with ethyl acetate (5mL) once more, evaporate the solvent to obtain a crude product, and purify it by column chromatography (PE:EA=4:1, v / v) to obtain intermediate III-a. Add III-a (52.2mg, 0.1mmol) and trifluoroacetic acid (31μL, 0.4mmol) to Schlenk, add anhydrous toluene (1.0mL), slowly drop boron trifluoride ether solution (126μL, 1mmol) to the reaction bottle, move to 60℃, and react for 12h. Add water (2mL) to quench, extract with ethyl acetate (3mL×3), and remove the solvent under reduced pressure to obtain crude IV-a. Column chromatography gave 42.3mg of white solid (PE:EA=10:1, yield 95%, dr value>20:1, ee value>99%.

[0088] Spectral data:

[0089] [α] D 25 -882 (c 0.14, CHCl3); 1 H NMR (400MHz, CDCl3): δ7.69(d,J=8.9Hz,2H),7.63(d,J=8.1Hz,2H),7.33–7.12(m,10H),7.00(d, J=7.3Hz,4H),5.08(dd,J=12.8,5.3Hz,2H),2.86(dd,J=13.4,5.3Hz,2H),2.56(t,J=13.2Hz,2H); 13 C NMR (101MHz, CDCl3): δ146.3,146.2,137.1,130.5,130.2,129.1,128.7,128.0,12 7.3,126.7,125.9,124.3,118.7,117.0,44.6,44.2,34.3.HRMS(ESI+):calcd.for C 37 H 26 O + [M+H] + 487.2057,found487.2052.

[0090] HPLC analysis: CHIRALPAK IB column, n-Hexane / EtOH=99:1, flow rate 1.0mL / min, uv-vis detection atλ=254nm,t major =5.25min,t minor =5.97min (major diastereomer).

[0091] Example 6

[0092] According to the preparation method of Example 5, only the reaction conditions were changed to prepare the chiral spirodihydroquinone derivatives shown below:

[0093]

[0094] The yield and structural identification data of the compound shown in formula IV-b:

[0095] White solid, yield 87%, dr value>20:1, ee value>99%, specific rotation: [α] D 25 -929 (c 0.10, CHCl3); 1 H NMR (300MHz, CDCl3): δ7.71(d,J=9.0Hz,2H),7.64(d,J=8.2Hz,2H),7.34–7.18(m,4H),7.14–6.97(m, 8H),5.05(dd,J=12.7,5.4Hz,2H),2.84(dd,J=13.4,5.3Hz,2H),2.55(t,J=13.2Hz,2H),2.33(s,6H); 13 C NMR (75MHz, CDCl3): δ146.2,143.1,137.3,136.2,130.5,130.2,129.3,128.9,127.9,127. 2,125.8,124.3,118.8,117.0,44.2(d,J=3.3Hz),33.7,27.1,21.2.HRMS(ESI+):calcd.for C 39 H 30 O + [M+H] + 515.2370, found 515.2362.

[0096] HPLC conditions: CHIRALPAK IB column, n-Hexane / EtOH=99.5:0.5, flow rate 1.0mL / min, uv-vis detection atλ=210nm, tmajor =5.06min,t minor =5.61min (major diastereomer).

[0097] The yield and structural identification data of the compound shown in formula IV-c:

[0098] White solid, yield 75%, dr value>20:1, ee value>99%, specific rotation: [α] D 25 -788 (c 0.12, CHCl3); 1 H NMR (300MHz, CDCl3): δ7.70(d,J=8.9Hz,2H),7.64(d,J=8.1Hz,2H),7.30–7.17(m,4H),7.17–7.04(m,4H ),7.02–6.88(m,6H),5.04(dd,J=12.6,5.3Hz,2H),2.82(dd,J=13.4,5.4Hz,2H),2.51(t,J=13.2Hz,2H); 13 C NMR (75MHz, CDCl3): δ161.7 (J=243.1Hz), 146.4, 141.8 (J=3.2Hz), 136.8, 130.4, 130.3 (J=3.0Hz), 130.2 ,128.1,127.3,126.2,124.3,118.5,117.1,115.5(J=25.6Hz),44.3,43.9,34.2.HRMS(ESI+):calcd.forC 37 H 24 F2O + [M+H] + 523.1868, found 523.1870.

[0099] HPLC conditions: CHIRALPAK IB column, n-Hexane / i-PrOH=85:15, flow rate 1.0mL / min, uv-vis detection atλ=210nm, t major =29.79min,t minor =17.90min (major diastereoisomer). (The liquid phase result of Vc is replaced by intermediate III-c)

[0100] The yield and structural identification data of the compound shown in formula IV-d:

[0101] White solid, yield 78%, dr value>20:1, ee value>99%, specific rotation: [α] D25 -943 (c 0.15, CHCl3); 1 H NMR (400MHz, CDCl3): δ7.70(d,J=8.9Hz,2H),7.64(d,J=8.1Hz,2H),7.35(d,J=8.6Hz,4H),7.23(dd,J=17.0,8.3Hz,4 H),6.97(dd,J=18.1,7.8Hz,4H),4.98(dd,J=12.7,5.3Hz,2H),2.77(dd,J=13.4,5.3Hz,2H),2.46(t,J=13.2Hz,2H); 13 C NMR (101MHz, CDCl3): δ146.4,145.2,136.2,131.7,130.7,130.3,130.2,128.1,12 7.3,126.2,124.3,120.4,118.3,117.2,44.1,44.0,34.2.HRMS(ESI+):calcd.for C 37 H 24 79 Br2O + [M+H] + 643.0267,found 643.0258.calcd.for C 37 H 26 81 Br2O + [M+H] + 647.0226, found 647.0218.

[0102] HPLC conditions: CHIRALPAK IF column, n-Hexane / i-PrOH=70:30, flow rate 1.0mL / min, uv-vis detection atλ=210nm, t major =8.92min,t minor = 18.94min (major diastereomer) (the liquid phase result of Vd was replaced by intermediate III-d).

[0103] The yield and structural identification data of the compound shown in formula IV-e:

[0104] White solid, yield 86%, dr value>20:1, ee value>99%, specific rotation: [α] D 25 -974 (c 0.25, CHCl3); 1H NMR (400MHz, CDCl3): δ7.70(d,J=9.0Hz,2H),7.63(d,J=8.1Hz,2H),7.30–7.20(m,4H),7.17(t,J=7.8Hz,2H),7. 06–6.95(m,8H),5.05(dd,J=12.7,5.3Hz,2H),2.85(dd,J=13.4,5.3Hz,2H),2.57(t,J=13.2Hz,2H),2.30(s,6H); 13 C NMR (101MHz, CDCl3): δ146.3,146.1,138.2,137.2,130.5,130.2,129.7,128.5,127.9,127. 4,127.3,126.2,125.9,124.3,118.8,117.0,44.5,44.2,34.3,21.5.HRMS(ESI+):calcd.for C 39 H 30 O + [M+H] + 515.2370, found 515.2365.

[0105] HPLC conditions: CHIRALPAK IF column, n-Hexane / i-PrOH=70:30, flow rate 1.0mL / min, uv-vis detection atλ=210nm,t major =7.01min,t minor =14.20min (major diastereoisomer). (The liquid phase result of Ve is replaced by intermediate III-e)

[0106] The yield and structural identification data of the compound shown in formula IV-f:

[0107] White solid, yield 76%, dr value>20:1, ee value>99%, specific rotation: [α] D 25 -774 (c 0.14, CHCl3); 1H NMR (400MHz, CDCl3): δ7.70(d,J=8.9Hz,2H),7.64(d,J=8.1Hz,2H),7.36–7.29(m,4H),7.23(d,J=6.3Hz,4H),7.12(t,J=7.8Hz,2H ),7.05(d,J=7.9Hz,2H),6.99(d,J=7.3Hz,2H),5.00(dd,J=12.6,5.4Hz,2H),2.81(dd,J=13.5,5.4Hz,2H),2.50(t,J=13.3Hz,2H); 13 CNMR (101MHz, CDCl3): δ148.6,146.4,135.9,131.9,130.3,130.3,130.2,129.9,128.1,1 27.8,127.4,126.3,124.4,122.7,118.2,117.2,44.4,44.0,34.2.HRMS(ESI+):calcd.for C 37 H 24 79 Br2O + [M+H] + 643.0267,found 643.0286.calcd.for C 37 H 26 81 Br2O + [M+H] + 647.0226, found 647.0219.

[0108] HPLC conditions: CHIRALPAK IF column, n-Hexane / i-PrOH=70:30, flow rate 1.0mL / min, uv-vis detection atλ=210nm,t major =7.51min,t minor =13.57min (major diastereoisomer). (The liquid phase result of Vf is replaced by intermediate III-f)

[0109] The yield and structural identification data of the compound shown in formula IV-g:

[0110] White solid, yield 72%, dr value>20:1, ee value>99%, specific rotation: [α] D 25 -834 (c 0.31, CHCl3); 1H NMR (400MHz, CDCl3): δ7.76(d,J=8.9Hz,2H),7.70(d,J=8.1Hz,2H),7.34–7.27(m,4H),7.22(ddd,J=9.8,3.5,1. 7Hz,6H),7.12–7.01(m,4H),5.07(dd,J=12.7,5.3Hz,2H),2.87(dd,J=13.5,5.4Hz,2H),2.57(t,J=13.3Hz,2H); 13 C NMR (101MHz, CDCl3): δ148.2,146.4,135.9,134.4,130.3,130.2,130.0,129.1,128.1,12 7.4,127.3,126.9,126.3,124.4,118.2,117.2,44.4,44.0,34.2.HRMS(ESI+):calcd.for C 37 H 24 35 Cl2O + [M+H] + 555.1277,found 555.1256.calcd.for C 37 H 26 37 Cl2O + [M+H] + 559.1218, found 559.1244.

[0111] HPLC conditions: CHIRALPAK IB column, n-Hexane / EtOAc=99:1, flow rate 1.0mL / min, uv-vis detection atλ=254nm,t major =20.02min,t minor =13.38min (major diastereomer).

[0112] The yield and structural identification data of the compound shown in formula IV-g:

[0113] White solid, yield 69%, dr value>20:1, ee value>99%, specific rotation: [α] D 25 -725 (c 0.12, CHCl3); 1H NMR (400MHz, CDCl3): δ7.74(d,J=8.9Hz,2H),7.66(d,J=8.1Hz,2H),7.35(t,J=1.9Hz,2H),7.33–7.20(m,4H),7.09(d,J=1.9Hz,4 H),7.03(dd,J=7.3,1.3Hz,2H),5.12(dd,J=12.9,4.6Hz,2H),2.90(dd,J=13.1,4.7Hz,2H),2.72(t,J=13.0Hz,2H),1.34(s,36H); 13 C NMR (101MHz, CDCl3): δ150.9,146.2,144.3,137.5,130.4,130.2,127.9,126.9,125.7,1 24.1,123.2,120.7,119.1,116.8,45.0,43.5,34.8,34.5,31.6.HRMS(ESI+):calcd.for C 53 H 58 O + [M+H] + 711.4561, found 711.4565.

[0114] HPLC conditions: CHIRALPAK IB column, n-Hexane / i-PrOH=95:5, flow rate 1.0mL / min, uv-vis detection atλ=210nm, t major =7.72min,t minor =9.12 min (major diastereomer). (The liquid phase result of Vh was replaced by intermediate III-h).

Claims

1. Two chiral spirodihydroquinone structures and derivative compounds thereof, characterized in that: The compound or enantiomer or racemate of which the structural formula is shown as A and the compound or enantiomer or racemate of which the structural formula is shown as B Wherein Ar is a substituted or unsubstituted phenyl group.

2. According to claim 1, the two chiral spirodihydrophene structures and their derivative compounds are characterized in that: Ar is phenyl, 4-methylphenyl, 4-fluorophenyl, 4-bromophenyl, 3-methylphenyl, 3-bromophenyl, 3-chlorophenyl or 3,5-di-tert-butylphenyl.

3. The asymmetric synthesis method of two chiral spirodihydroquinone structures and derivative compounds thereof according to claim 2, characterized in that: The following synthetic route is adopted: The following steps are involved: Step (1): Acetone undergoes a condensation reaction with different aromatic substituted aldehydes under alkaline conditions to generate compound I; Step (2): Under the catalysis of a chiral rhodium catalyst, compound I and arylboron reagent II undergo an asymmetric addition reaction to generate an intermediate III, which is separated and purified; when boron trifluoride etherate and potassium phosphate are added, intermediate III undergoes an intramolecular Friedel-Crafts reaction to prepare compound IV; boron trifluoride etherate and trifluoroacetic acid are added to generate compound V; a mixture of compound IV and V is prepared by adding only boron trifluoride etherate; Ar is phenyl, 4-methylphenyl, 4-fluorophenyl, 4-bromophenyl, 3-methylphenyl, 3-bromophenyl, 3-chlorophenyl, 3.5-di-tert-butylphenyl; Wherein: the chiral rhodium catalyst used in step (2) has the structural formula of [RhCl(L)x]2, x=1 / 2, wherein the chiral ligand L is any one of the following structures:

4. The method according to claim 3, characterized in that: In step (1), the alkaline condition is an inorganic alkali aqueous solution, wherein the inorganic alkali is one or more of potassium carbonate, cesium carbonate, tripotassium phosphate, lithium hydroxide, sodium hydroxide and potassium hydroxide aqueous solution; the mass fraction of the inorganic alkali aqueous solution is 30-60%; the molar ratio of the arylboron reagent II, acetone and the inorganic base is 2-5:1:3-5; the reaction temperature of step (1) is 0-50°C; the reaction time is 6-12h; the reagent I is any one of the following structures:

5. The method according to claim 3, characterized in that: In step (2), the solvent used in preparing the aryl boron reagent II is one or more of tetrahydrofuran, 1,2-dichloroethane, 1,4-dioxane, toluene, methyl tert-butyl ether, N,N-dimethylformamide and water; the molar ratio of compound I, aryl boron reagent II and chiral rhodium catalyst is 1:1-5:0.005-0.05, the reaction temperature for converting compound I into aryl boron reagent II is 40-100°C, and the reaction time is 10-16h.

6. The method according to claim 3, characterized in that: When compound III is converted to compound IV in step (2), the added boron trifluoride etherate is 5-10 molar equivalents and the added potassium phosphate is 1-2 molar equivalents.

7. The method according to claim 7, characterized in that: When compound III is converted to compound V in step (2), the added boron trifluoride etherate is 5-10 molar equivalents and the added trifluoroacetic acid is 4-5 molar equivalents.

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