Preparation method of chiral aryloxy substituted chiral diol

Abstract

The invention discloses a preparation method of chiral aryloxy substituted chiral diol, which comprises the following step: in the presence of a chiral catalyst and a transfer hydrogenation reagent, carrying out selective transfer hydrogenation reaction on aryloxy substituted asymmetric diketone to generate the chiral aryloxy substituted chiral diol. According to the method provided by the invention, the raw materials and the catalyst are cheap and easy to obtain, the reaction condition is mild, the operation is simple, and the reaction is efficient; through asymmetric transfer hydrogenation of aryloxy-substituted asymmetric diketone, the chiral aryloxy-substituted chiral diol core skeleton is prepared with high selectivity, the synthesis route is direct, and the atom economy is high.

Description

TECHNICAL FIELD

[0001] The application relates to a preparation method of a chiral aryloxy-substituted chiral diol, and belongs to the field of chemical synthesis. BACKGROUND

[0002] Chiral triols are widely present in many natural products and bioactive molecules, for example, the polyphenol and glycerol natural products shown in the following formula all have 1,2,3-chiral triol structures, and these natural products have good anticancer, antibacterial, anti-diabetic, anti-inflammatory, antithrombotic, antiviral, anti-herpes simplex virus, and neuroprotective and immunomodulatory properties.

[0003]

[0004] At present, there are few reports on the catalytic asymmetric synthesis method of the above-mentioned natural products in the literature. The asymmetric Sharpless dihydroxylation reaction of allyl alcohol can only be used for the synthesis of glycerol natural products with two stereocenters in cis (eq 1), and it is difficult to prepare polyphenol compounds with three stereocenters. Therefore, developing alternative methods to obtain the skeleton of the above-mentioned natural products and stereoisomers is a great challenge for chemists and a scientific problem that needs to be solved in the field of asymmetric synthesis. In this patent, we plan to prepare the skeleton structure of the polyphenol compound with (anti, syn) chirality (eq 2).

[0005] SUMMARY

[0006] In view of the above, the purpose of the present application is to provide a method for preparing a chiral aryloxy-substituted chiral diol. The method uses a chiral metal complex as a catalyst, and uses a non-chiral aryloxy-substituted asymmetric diketone as a starting material, and realizes selective transfer hydrogenation in the presence of a transfer hydrogenation reagent, thereby obtaining the core skeleton of the chiral aryloxy-substituted chiral diol.

[0007] According to the present application, a method for preparing a chiral aryloxy-substituted chiral diol is provided, comprising:

[0008] In the presence of a chiral catalyst and a transfer hydrogenation reagent, the chiral aryloxy-substituted chiral diol is generated by selective transfer hydrogenation reaction from an aryloxy-substituted asymmetric diketone;

[0009] The aryloxy-substituted asymmetric diketone has the structure shown in formula II:

[0010]

[0011] The chiral aryloxy-substituted chiral diol has the structure shown in formula I:

[0012]

[0013] wherein R 1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.

[0014] R 2 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.

[0015] In some embodiments, R 1 is selected from the group consisting of C5-C 20 aryl, C5-C 20 substituted aryl, C4-C 20 heteroaryl, and C4-C 20 substituted heteroaryl.

[0016] R 2 is selected from the group consisting of C1-C 20 alkyl, C1-C 20 substituted alkyl, C5-C 20 aryl, C5-C 20 substituted aryl, C4-C 20 heteroaryl, and C4-C 20 substituted heteroaryl.

[0017] In some embodiments, R 1 is selected from the group consisting of C5-C 10 aryl, C5-C 10 substituted aryl, C4-C 10 heteroaryl.

[0018] R 2 is selected from the group consisting of C1-C 10 alkyl, C1-C 10 substituted alkyl, C5-C 10 aryl, C5-C 10 substituted aryl, C4-C 10 heteroaryl.

[0019] In some embodiments, the C1-C 10 alkyl of the alkyl group comprises a straight chain alkyl group of C1-C 10 , a branched chain alkyl group of C3-C 10 , and a cyclic alkyl group of C3-C 10 .

[0020] In the present application, Ar represents aryl or substituted aryl, which means any functional group or substituent derived from an aromatic ring or an aromatic ring containing a substituent; in some embodiments, Ar is selected from the group consisting of C5-C 20 aryl, or C5-C 20 substituted aryl.

[0021] In some embodiments, each of the substituents in the substituted alkyl, substituted aryl or substituted heteroaryl is independently selected from C1-C 20 hydrogen, C1-C 20 heteroaryl or non-hydrocarbon group;

[0022] In some embodiments, the non-hydrocarbon group is selected from oxygen, halogen, a group having a structure represented by Formula (1), a group having a structure represented by Formula (2) or a group having a structure represented by Formula (3):

[0023]

[0024] wherein M 11 , M 21 and M 31 are independently selected from hydrogen or C1-C 10 alkyl.

[0025] In some embodiments, the non-hydrocarbon group comprises oxygen, halogen, hydroxyl, C1-C 10 carboxyl, C1-C 10 ester, C1-C 10 alkoxy, C5-C 10 aryloxy and C1-C 10 acyloxy.

[0026] In some embodiments, the halogen comprises F, Cl, Br and I.

[0027] In some embodiments, the chiral catalyst is selected from a chiral metal complex-based catalyst.

[0028] In some embodiments, the chiral catalyst is selected from at least one of a chiral ruthenium (Ru) complex-based catalyst.

[0029] In some embodiments, the chiral catalyst is selected from at least one of the following catalysts C1-C11:

[0030]

[0031] In some embodiments, the molar ratio of the aryl-substituted unsymmetrical diketone to the chiral catalyst is 1:(0.02-0.06).

[0032] In some embodiments, the molar ratio of the aryl-substituted unsymmetrical diketone to the chiral catalyst is 1:(0.03-0.05).

[0033] In some embodiments, the molar ratio of the aryloxy-substituted unsymmetrical diketone to the chiral catalyst is independently selected from any value or range between any two values of 1 :0.030, 1 :0.031, 1 :0.032, 1 :0.033, 1 :0.034, 1 :0.035, 1 :0.036, 1 :0.037, 1 :0.038, 1 :0.039, 1 :0.040, 1 :0.041, 1 :0.042, 1 :0.043, 1 :0.044, 1 :0.045, 1 :0.046, 1 :0.047, 1 :0.048, 1 :0.049, 1 :0.050.

[0034] In some embodiments, the transfer hydrogenation reagent is selected from at least one of ammonium formate, sodium formate, isopropanol, formic acid / amine azeotrope.

[0035] In some embodiments, the formic acid / amine azeotrope is selected from at least one of formic acid / ethylamine, formic acid / n-propylamine, formic acid / isopropylamine, formic acid / n-butylamine, formic acid / t-butylamine, formic acid / dimethylamine, formic acid / diethylamine, formic acid / diisopropylamine, formic acid / tetramethylethylenediamine, formic acid / trimethylamine, formic acid / triethylamine.

[0036] In some embodiments, the transfer hydrogenation reagent is formic acid / tetramethylethylenediamine.

[0037] In some embodiments, the molar ratio of the transfer hydrogenation reagent to the aryloxy-substituted unsymmetrical diketone is (5-20): 1.

[0038] In some embodiments, the molar ratio of the transfer hydrogenation reagent to the aryloxy-substituted unsymmetrical diketone is selected from any value or range between any two values of 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1.

[0039] In some embodiments, the molar ratio of the transfer hydrogenation reagent to the aryloxy-substituted unsymmetrical diketone is (8-16): 1.

[0040] wherein the amine in the transfer hydrogenation reagent is used to assist the formic acid to generate hydrogen source, and the formic acid is used as the hydrogen source, and when the transfer hydrogenation reagent is formic acid / amine azeotrope, the molar ratio of the transfer hydrogenation reagent to the aryloxy-substituted unsymmetrical diketone is calculated based on the amount of substance of the formic acid.

[0041] In some embodiments, the volume ratio of the formic acid to the amine in the formic acid / amine azeotrope is 5:1-4.

[0042] In some embodiments, the volume ratio of formic acid to amine in the formic acid / amine azeotrope is independently selected from any value or a range between any two values selected from the group consisting of 5: 1.0, 5: 1.5, 5: 2.0, 5: 2.2, 5: 2.5, 5: 2.7, 5: 3.0, 5: 3.3, 5: 3.5, 5: 3.8, 5: 4.0.

[0043] In some embodiments, a solvent can also be included in the reaction system, which can be an additional solvent different from the raw material aryl-oxy-substituted unsymmetrical diketone and the transfer hydrogenation reagent.

[0044] In some embodiments, the solvent is at least one selected from the group consisting of acetonitrile, dichloromethane, dimethyl sulfoxide, ethyl acetate, and isopropanol.

[0045] In some embodiments, the selective transfer hydrogenation reaction of the aryl-oxy-substituted unsymmetrical diketone of the present application can occur without the need for additional solvents.

[0046] In some embodiments, the reaction temperature of the reaction is 10-50°C, and the reaction time is 15-35h.

[0047] In some embodiments, the reaction temperature of the reaction is independently selected from any value or a range between any two values selected from the group consisting of 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, and 45°C.

[0048] In some embodiments, the reaction time of the reaction is independently selected from any value or a range between any two values selected from the group consisting of 20h, 21h, 22h, 23h, 24h, 25h, 26h, 27h, 28h, 29h, and 30h.

[0049] In some embodiments, the reaction temperature of the reaction is 30-45°C, and the reaction time is 20-30h.

[0050] The inventors have found that the yield of the product is improved at this reaction temperature and reaction time, and that a higher or lower reaction temperature or a shorter reaction time can cause the generation of more other products.

[0051] In some embodiments, the method further comprises a step of separating and purifying the chiral aryl-oxy-substituted chiral diol.

[0052] In some embodiments, the method comprises the following steps:

[0053] a) placing a mixture comprising the aryl-oxy-substituted unsymmetrical diketone, the transfer hydrogenation reagent, and the chiral catalyst in a reaction vessel, stirring at 10-50°C for 15-35h to perform the transfer hydrogenation reaction, to obtain a reaction product;

[0054] b) extracting the reaction product and concentrating the obtained organic phase to obtain a crude chiral aryloxy-substituted chiral diol;

[0055] c) purifying the crude product by silica gel column chromatography to obtain purified chiral aryloxy-substituted chiral diol.

[0056] In some embodiments, the concentrating comprises drying over anhydrous sodium sulfate and rotary evaporation.

[0057] In some embodiments, the concentrating is performed under reduced pressure.

[0058] The beneficial effects of this application include:

[0059] 1) The method provided in this application has cheap and readily available raw materials and catalysts, mild reaction conditions, simple operation, and high reaction efficiency.

[0060] 2) The method provided in the present application is to prepare a chiral aryloxy-substituted chiral diol core skeleton with high selectivity through asymmetric transfer hydrogenation of aryloxy-substituted asymmetric diketone. The synthetic route is direct and atom economy is high. DETAILED DESCRIPTION

[0061] Definitions: Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0062] In this application, the expression "C1-C 10 ”, “C1-C 20 ” etc. refer to the number of carbon atoms contained in the group.

[0063] In the present application, the term "hydrocarbon group" refers to a group formed by losing any hydrogen atom on a hydrocarbon compound molecule, and the hydrocarbon compounds include alkane compounds, olefin compounds, alkyne compounds and aromatic compounds, and the corresponding groups formed include alkyl, alkenyl, alkynyl and aryl groups; for example, toluene loses the hydrogen atom in the para position of the methyl group on the benzene ring to form p-tolyl, or toluene loses any hydrogen atom on the methyl group to form benzyl, etc.

[0064] In this application, the term "alkyl" refers to a saturated hydrocarbon group, which is a group formed by losing any hydrogen atom from an alkane compound molecule. In this application, alkyl includes straight-chain alkyl, branched-chain alkyl and cycloalkyl.

[0065] In the present application, the term "aryl" refers to a group formed by losing a hydrogen atom on an aromatic ring of an aromatic compound molecule, such as p-tolyl formed by toluene losing a hydrogen atom at the para position of the methyl group on the benzene ring.

[0066] In the present application, the term "heteroaryl" refers to a group formed by losing one hydrogen atom from a heteroaromatic compound (heteroaromatic compound for short) molecule, which contains O, N or S heteroatom in the aromatic ring, for example, a furan group formed by losing one hydrogen atom from a furan ring.

[0067] In the present application, the term "halogen" refers to at least one of fluorine, chlorine, bromine and iodine.

[0068] In the present application, the term "non-hydrocarbon group" refers to a group formed by losing one hydrogen atom from a compound containing other elements (such as halogen, S, O, P, N, etc.) in addition to H and C; some non-limiting examples include alkoxy, carboxyl, hydroxyl, ester, halogen, sulfonic acid, amino, nitro, etc.

[0069] In the present application, the term "alkoxy", usually represented by RO-, is composed of one alkyl and one oxygen atom.

[0070] In the present application, the term "aryloxy" can be analogous to alkoxy, and aryl oxy is a group formed by connecting oxygen to an aromatic group, such as ph-O-.

[0071] In the present application, the definition of the number of carbon atoms in the "substituted alkyl", "substituted aryl" and "substituted heteroaryl" refers to the number of carbon atoms contained in the corresponding hydrocarbon group and heteroaromatic group itself, not the number of carbon atoms after substitution. For example, "C1-C10 substituted alkyl" refers to at least one hydrogen atom on an alkyl group with 1-10 carbon atoms being replaced by a substituent, such as a group with 11 carbon atoms formed by replacing one hydrogen on an adamantyl group with C≡N. 10

[0072] In the present application, the "substitution" includes the substitution of at least one hydrogen atom, and can also be the substitution of two or more hydrogen atoms. The two or more hydrogen atoms can be hydrogen atoms on the same carbon atom or different carbon atoms.

[0073] In the present application, "transfer hydrogenation reagent" can also be used interchangeably with "hydrogen transfer reagent", "hydrogen atom transfer reagent" and the like in the art; it generally means a reagent used to introduce and / or remove hydrogen atoms, thereby changing the structure and properties of the molecule.

[0074] In the present application, "chiral catalyst" means a compound with chiral structure, which can help control the stereochemical configuration of the product in chemical reactions, and improve the selectivity and efficiency of the reaction.

[0075] The present application will be described in detail below with reference to examples, but the present application is not limited to these examples.

[0076] Unless otherwise specified, the raw materials and catalysts in the examples of the present application are purchased through commercial channels. ​

[0077] The instruments used in the examples of this application are as follows:

[0078] The nuclear magnetic resonance was measured using Bruker 400AVANCE III and 600AVANCE III spectrometers, and the hydrogen spectrum ( 1 H-NMR): 400MHz or 600MHz, CDCl3; carbon spectrum ( 13 C-NMR): 101 MHz or 151 MHz, CDCl3. High-performance liquid chromatography (HPLC) was measured using a Shimadzu LC-20AD workstation. High-resolution mass spectrometry (HRMS) was performed using an Agilent 6540Q-TOF instrument. Infrared spectroscopy (IR) was performed using a Bruker VERTEX 70 instrument.

[0079] The yield of the protected chiral aryloxy-substituted chiral diol is based on the amount of aryloxy-substituted asymmetric diketone and is calculated by the following formula:

[0080] Yield % = (actual mass of target product obtained ÷ theoretical mass of target product) × 100%

[0081] The meanings of the abbreviations that may be involved in the examples of the present application are as follows: Me is methyl; Ph is phenyl; PMP is p-methoxyphenyl; HCOOH is formic acid; TMEDA is tetramethylethylenediamine; NMR is nuclear magnetic resonance; chiral HPLC is high performance liquid chromatography equipped with a chiral chromatographic column; ee value is the enantiomeric excess ratio; TLC is thin layer chromatography.

[0082] In the description of the embodiments of the present application, the amount of catalyst used is expressed as the molar percentage of the molar number of catalyst relative to the molar number of aryloxy-substituted asymmetric diketone; the amount of transfer hydrogenation reagent used is expressed as the molar equivalent of transfer hydrogenation reagent relative to the molar number of aryloxy-substituted asymmetric diketone.

[0083] Example 1

[0084]

[0085] A mixture of formic acid and tetramethylethylenediamine (98 μL, n:n=5:2, 10.0 equiv) was dissolved in acetonitrile (1 mL), and aryloxy-substituted unsymmetrical diketone 1-1 (36.0 mg, 0.1 mmol) and Ru catalyst C8 (2.6 mg, 4 mol%) were added to the above solution, which was stirred at 35 °C for 24 h. After the completion of the reaction was confirmed by TLC spotting, the reaction mixture was extracted with ethyl acetate (3 x 5 mL), and the resulting organic phase was dried over anhydrous sodium sulfate and then rotary-evaporated to give the crude product. The resulting crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1, v / v). The resulting product sample was noted as 1-2, 31.0 mg in total, with a yield of 85%, an ee value of 99%, and a 79:9:8:4 dr.

[0086] The detection data of product sample 1-2 are as follows:

[0087] colorless oily liquid; 1 H NMR (400 MHz, CDC13) δ 7.42-7.35 (m, 4H), 7.33-7.28 (m, 3H), 7.18 (d, J = 7.8 Hz, 2H), 6.81-6.77 (m, 2H), 6.73-6.70 (m, 2H), 5.19 (d, J = 5.9 Hz, 1H), 5.04 (s, 1H), 4.03 (s, 1H), 3.71 (s, 3H), 3.07 (d, J = 3.8 Hz, 1H), 2.36-2.31 (m, 4H); 13 C NMR (101 MHz, CDC13) δ 154.4, 151.7, 141.5, 138.2, 134.9, 129.6, 128.5, 127.8, 127.2, 126.4, 117.3, 114.7, 82.3, 77.9, 72.0, 55.7, 21.3. HRMS (ESI-Quadrupole-Orbitrap) m / z: [M + Na] + Calcd for C 23 H 24 O4Na 387.1567; Found 387.1566. [a] D 25 +24.0 (c 0.15, CHCl3); HPLC analysis: 99% ee (Chiralcel IC, 10:90 i PrOH / hexanes, 1 mL / min, 254 nm), R t (major) = 20.3 min, R t (minor) = 10.3 min. IR (KBr thin film, cm-1 ): v 3284, 2921, 1503, 1225, 1103, 1033, 1019, 813, 744, 710, 599, 518.

[0088] Example 2

[0089]

[0090] A mixture of formic acid and tetramethylethylenediamine (98 μL, n:n = 5:2, 10.0 equiv) was dissolved in acetonitrile (1 mL), and aryloxy-substituted unsymmetrical diketone 2-1 (39.0 mg, 0.1 mmol) and Ru catalyst C8 (2.6 mg, 4 mol%) were added to the above solution, which was stirred at 35 °C for 24 h. After the completion of the reaction was confirmed by TLC spotting, the reaction system was extracted with ethyl acetate (3 x 5 mL), and the obtained organic phase was dried over anhydrous sodium sulfate and then rotary evaporated to obtain the crude product. The obtained crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1, v / v). The obtained product sample was noted as 2-2, 31.2 mg in total, with a yield of 79%, an ee value of 97%, and a 72:14:7:7 dr.

[0091] The detection data of product sample 2-2 are as follows:

[0092] Colorless oily liquid; 1 H NMR (400 MHz, CDC13) δ 7.40-7.27 (m, 5H), 6.93 (d, J = 1.3 Hz, 1H), 6.87-6.72 (m, 6H), 5.95 (s, 2H), 5.10 (d, J = 6.2 Hz, 1H), 5.05 (d, J = 1.7 Hz, 1H), 4.00 (dd, J = 5.9, 1.9 Hz, 1H), 3.72 (s, 3H), 3.00 (br, 1H), 2.33 (br, 1H); 13 C NMR (151 MHz, CDC13) δ 154.5, 151.5, 148.3, 147.7, 141.4, 131.9, 128.6, 127.9, 126.5, 121.1, 117.4, 114.7, 108.5, 107.5, 101.3, 81.9, 77.8, 72.1, 55.8. HRMS (ESI-Quadrupole-Orbitrap) m / z: [M + Na] + Calcd for C 23 H 22 O6Na 417.1309; Found 417.1307. [a] D 25+9.0 (c 1.8, CHCl3); HPLC analysis: 97% ee (Chiralcel IC, 25:75 i PrOH / hexanes, 1 mL / min, 254 nm), R t (major) = 9.5 min, R t (minor) = 5.3 min. IR (KBr thin film, cm -1 ): v 2922, 1612, 1505, 1453, 1265, 1224, 1180, 1036, 822, 700.

[0093] Example 3

[0094]

[0095] A mixture of formic acid and tetramethylethylenediamine (98 μL, n:n = 5:2, 10.0 equiv) was dissolved in acetonitrile (1 mL), and arlyoxy-substituted unsymmetrical diketone 3-1 (35.2 mg, 0.1 mmol) and Ru catalyst C8 (2.6 mg, 4 mol%) were added to the above solution, and the reaction was stirred at 35 °C for 24 h. After the completion of the reaction was confirmed by TLC spotting, the reaction was extracted with ethyl acetate (3 x 5 mL), and the obtained organic phase was dried over anhydrous sodium sulfate and then rotary evaporated to obtain the crude product. The obtained crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1, v / v). The obtained product sample was designated as 3-2, and the yield was 72% (25.6 mg), the ee value was 99%, and the dr value was 72:12:11:0.

[0096] The detection data of product sample 3-2 are as follows:

[0097] colorless oily liquid; 1 H NMR (400 MHz, CDC13) δ 7.39 - 7.33 (m, 5 H), 7.32 - 7.27 (m, 2 H), 7.15 (d, J = 5.0 Hz, 1 H), 6.83 - 6.79 (m, 2 H), 6.76 - 6.72 (m, 2 H), 5.25 (d, J = 5.6 Hz, 1 H), 4.97 (d, J = 3.1 Hz, 1 H), 4.09 (dd, J = 5.6, 3.1 Hz, 1 H), 3.72 (s, 3 H), 1.77 (br, 2 H); 13C NMR (101 MHz, CDC13) δ 154.5, 151.6, 141.1, 139.3, 128.6, 127.9, 126.7, 126.5, 126.4, 123.5, 117.5, 114.6, 79.1, 72.3, 55.7. HRMS (ESI-Quadrupole-Orbitrap) m / z: [M + Na] + Calcd for C 20 H 20 O4SNa 379.0975; Found 379.0972. [a] D 25 + 17.7 (c 1.5, CHCl3); HPLC analysis: 99% ee (Chiralcel OJ-H, 20:80 i PrOH / hexanes, 1 mL / min, 254 nm), R t (major) = 16.0 min, R t (minor) = 23.7 min. IR (KBr thin film, cm -1 ): v 3053, 1610, 1505, 1380, 1264, 1222, 1171, 1026, 826, 697.

[0098] Example 4

[0099]

[0100] A mixture of formic acid and tetramethylethylenediamine (98 μL, n:n=5:2, 10.0 equiv) was dissolved in acetonitrile (1 mL), and arlyoxy-substituted unsymmetrical diketone 4-1 (38.0 mg, 0.1 mmol) and Ru catalyst C8 (2.6 mg, 4 mol%) were added to the above solution, and the reaction was stirred at 35 °C for 24 h. After the completion of the reaction was confirmed by TLC spotting, the reaction system was extracted with ethyl acetate (3 x 5 mL), and the obtained organic phase was dried over anhydrous sodium sulfate and then rotary evaporated to obtain the crude product. The obtained crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1, v / v). The obtained product sample was recorded as 4-2, 29.0 mg in total, with a yield of 76%, ee value of 98%, and 92:8:0:0 dr.

[0101] The detection data of product sample 4-2 are as follows:

[0102] White solid, mp 195-197 °C; 1H NMR (400 MHz, CDC13) δ 7.42 - 7.35 (m, 4 H), 7.34 - 7.30 (m, 5 H), 6.81 - 6.78 (m, 2 H), 6.74 - 6.72 (m, 2 H), 5.22 (d, J = 5.9 Hz, 1 H), 5.03 (s, 1 H), 3.98 (d, J = 5.2 Hz, 1 H), 3.71 (s, 3 H), 3.10 (br, 1 H), 2.35 (br, 1 H); 13 C NMR (101 MHz, CDC13) δ 154.6, 151.5, 140.0, 137.9, 133.5, 129.0, 128.63, 128.59, 127.8, 127.2, 117.3, 114.7, 82.6, 77.8, 71.4, 55.8. HRMS (ESI-Quadrupole-Orbitrap) m / z: [M+Na] + Calcd for C 22 H 21 04ClNa 407.1021; Found 407.1019. [a] D 28 +1.1 (c 2.5, CHCl3); HPLC analysis: 98% ee (Chiralcel IC, 5:95 i PrOH / hexanes, 1 mL / min, 220 nm), R t (major) = 17.5 min, R t (minor) = 11.1 min. IR (KBr thin film, cm -1 ): v 3256, 2930, 1503, 1491, 1219, 1092, 1036, 1023, 1012, 828, 792, 754, 700.

[0103] Example 5

[0104]

[0105] A mixture of formic acid and tetramethylethylenediamine (98 μL, n:n = 5:2, 10.0 equiv) was dissolved in acetonitrile (1 mL), to the above solution was added aryloxy substituted unsymmetrical diketone 5-1 (36.0 mg, 0.1 mmol) and Ru catalyst C8 (2.6 mg, 4 mol%), the reaction was stirred at 35 °C for 24 h. After the completion of the reaction was confirmed by TLC spotting, the reaction was extracted with ethyl acetate (3 x 5 mL), the obtained organic phase was dried over anhydrous sodium sulfate and then rotary evaporated to get the crude product. The obtained crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1, v / v). The obtained product sample was noted as 5-2, 29.5 mg, 81% yield, 98% ee, 87:8:5:0 dr.

[0106] The analytical data of product sample 5-2 is as follows:

[0107] White solid, mp 90-92 °C; 1 H NMR (400 MHz, CDC13) δ 7.43-7.41 (m, 2H), 7.38-7.35 (m, 2H), 7.33-7.31 (m, 1H), 7.29-7.27 (m, 1H), 7.26-7.25 (m, 1H), 7.17-7.12 (m, 2H), 6.81-6.78 (m, 2H), 6.73-6.71 (m, 2H), 5.19 (d, J = 5.9 Hz, 1H), 4.99 (d, J = 2.4 Hz, 1H), 4.03 (dd, J = 5.9, 2.5 Hz, 1H), 3.71 (s, 3H), 2.34 (s, 3H); 13 C NMR (101 MHz, CDC13) δ 154.4, 151.6, 138.3, 138.1, 137.5, 129.2, 128.8, 128.4, 127.3, 126.4, 117.3, 114.6, 82.3, 77.9, 71.9, 55.7, 21.3. HRMS (ESI-Quadrupole-Orbitrap) m / z: [M + Na] + Calcd for C 23 H 24 O4Na 387.1567; Found 387.1567. [a] D 25 +18.4 (c 0.4, CHCl3); HPLC analysis: 98% ee (Chiralcel OJ-H, 20:80 i PrOH / hexanes, 1 mL / min, 254 nm), R t (minor) = 9.0 min, Rt (minor) = 14.5 min. IR (KBr thin film, cm -1 ): v 2924, 1607, 1505, 1264, 1223, 1104, 1036, 896, 702.

[0108] Example 6

[0109]

[0110] A mixture of formic acid and tetramethylethylenediamine (98 μL, n:n = 5:2, 10.0 equiv) was dissolved in acetonitrile (1 mL), and aryloxy-substituted unsymmetrical diketone 6-1 (39.6 mg, 0.1 mmol) and Ru catalyst C8 (2.6 mg, 4 mol%) were added to the above solution, which was stirred at 35 °C for 24 h. After the completion of the reaction was confirmed by TLC spotting, the reaction system was extracted with ethyl acetate (3 x 5 mL), and the obtained organic phase was dried over anhydrous sodium sulfate and then rotary evaporated to obtain the crude product. The obtained crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1, v / v). The obtained product sample was recorded as 6-2, 33.0 mg in total, with a yield of 83%, ee value of 99%, and 76:17:7:0 dr.

[0111] The detection data of product sample 6-2 are as follows:

[0112] colorless oily liquid; 1 H NMR (400 MHz, CDCl3) δ 7.86-7.81 (m, 4H), 7.50-7.44 (m, 5H), 7.38 (t, J = 7.3 Hz, 2H), 7.34-7.30 (m, 1H), 6.85-6.78 (m, 2H), 6.74-6.69 (m, 2H), 5.26 (d, J = 6.0 Hz, 1H), 5.22 (d, J = 0.8 Hz, 1H), 4.14 (dd, J = 5.8, 1.9 Hz, 1H), 3.71 (s, 3H), 3.21 (br, 1H), 2.42 (br, 1H); 13 C NMR (101 MHz, CDCl3) δ 154.4, 151.6, 138.8, 138.1, 133.3, 133.1, 128.9, 128.5, 128.3, 128.1, 127.8, 127.3, 126.3, 126.1, 125.3, 124.4, 117.4, 114.7, 82.5, 77.8, 72.1, 55.7. HRMS (ESI-Quadrupole-Orbitrap) m / z: [M + Na] + Calcd for C26 H 24 O4Na423.1567; Found 423.1567.[α] D 25 +24.1 (c 0.5, CHCl3); HPLC analysis: 99% ee (Chiralcel IC, 25:75 i PrOH / hexanes, 1 mL / min, 254 nm), R t (major) = 10.1 min, R t (minor) = 5.2 min. IR (KBr thin film, cm -1 ): v 3056, 2931, 1602, 1507, 1453, 1265, 1222, 1103, 1036, 822, 700.

[0113] Example 7

[0114]

[0115] A mixture of formic acid and tetramethylethylenediamine (98 μL, n:n=5:2, 10.0 equiv) was dissolved in acetonitrile (1 mL), to the above solution was added aryloxy substituted unsymmetrical diketone 7-1 (35.2 mg, 0.1 mmol) and Ru catalyst C8 (2.6 mg, 4 mol%), the reaction was stirred at 35 °C for 24 h. After the completion of the reaction was confirmed by TLC spotting, the reaction was extracted with ethyl acetate (3 x 5 mL), the obtained organic phase was dried over anhydrous sodium sulfate and then rotary evaporated to give the crude product. The obtained crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1, v / v). The obtained product sample was noted as 7-2, 30.0 mg in total, with a yield of 84%, ee value of 99%, 82:10:8:0 dr.

[0116] The detection data of product sample 7-2 were as follows:

[0117] colorless oily liquid; 1H NMR (600 MHz, CDC13) δ 7.43 - 7.42 (m, 2H), 7.38 - 7.36 (m, 2H), 7.33 - 7.30 (m, 1H), 7.28 (dd, J = 5.1, 1.1 Hz, 1H), 7.06 (d, J = 3.3 Hz, 1H), 6.99 (dd, J = 5.0, 3.6 Hz, 1H), 6.81 - 6.78 (m, 2H), 6.74 - 6.71 (m, 2H), 5.29 (d, J = 2.2 Hz, 1H), 5.20 (d, J = 6.5 Hz, 1H), 4.11 (dd, J = 6.5, 2.4 Hz, 1H), 3.71 (s, 3H), 3.06 (br, 1H), 2.45 (br, 1H); 13 C NMR (151 MHz, CDC13) δ 154.5, 151.6, 144.8, 138.0, 128.9, 128.6, 127.4, 126.8, 125.5, 125.1, 117.4, 114.7, 81.8, 77.5, 68.9, 55.8. HRMS (ESI-Quadrupole-Orbitrap) m / z: [M+Na] + Calcd for C 20 H 20 O4SNa 379.0975; Found 379.0976. [a] D 25 +16.5 (c 1.3, CHCl3); HPLC analysis: 99% ee (Chiralcel IC, 20:80 i PrOH / hexanes, 1 mL / min, 254 nm), R t (major) = 10.3 min, R t (minor) = 5.2 min. IR (KBr thin film, cm -1 ): v 3054, 1608, 1505, 1453, 1264, 1224, 1037, 896, 702.

[0118] Example 8

[0119]

[0120] A mixture of formic acid and tetramethylethylenediamine (98 μL, n:n = 5:2, 10.0 equiv) was dissolved in acetonitrile (1 mL), and aryloxy-substituted unsymmetrical diketone 8-1 (66.4 mg, 0.1 mmol) and Ru catalyst C8 (2.6 mg, 4 mol%) were added to the above solution, which was stirred at 35 °C for 24 h. After the completion of the reaction was confirmed by TLC spotting, the reaction system was extracted with ethyl acetate (3 x 5 mL), and the obtained organic phase was dried over anhydrous sodium sulfate and then rotary evaporated to obtain the crude product. The obtained crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1, v / v). The obtained product sample was recorded as 8-2, 47.4 mg in total, with a yield of 71%, an ee value of 96%, and a 67:13:12:8 dr.

[0121] The detection data of product sample 8-2 are as follows:

[0122] colorless oily liquid; 1 H NMR (400 MHz, CDCl3) δ 7.43-7.32 (m, 16H), 7.24 (d, J = 8.6 Hz, 2H), 6.90 (d, J = 8.5 Hz, 2H), 6.77 (d, J = 9.1 Hz, 2H), 6.71 (d, J = 9.1 Hz, 2H), 6.62 (d, J = 1.8 Hz, 1H), 6.58 (d, J = 8.5 Hz, 1H), 5.71 (d, J = 5.0 Hz, 1H), 5.09 (s, 2H), 5.03 (s, 2H), 5.00 (s, 2H), 4.96 (s, 1H), 4.10 (s, 1H), 3.71 (s, 3H), 3.17 (s, 1H), 2.71 (d, J = 5.6 Hz, 1H); 13 C NMR (101 MHz, CDCl3) δ 159.9, 158.3, 156.8, 154.3, 151.6, 137.2, 136.8, 136.6, 134.0, 128.84, 128.78, 128.7, 128.3, 128.2, 128.1, 127.8, 127.7, 127.6, 127.3, 118.8, 116.9, 114.7, 114.6, 106.4, 100.7, 77.4, 76.7, 71.9, 70.32, 70.25, 70.1, 55.8. HRMS (ESI-Quadrupole-Orbitrap) m / z: [M + Na] + Calcd for C 43 H 40 O7Na 691.2666; Found 691.2662. [a] D 25+11.3 (c 0.7, CHCl3); HPLC analysis: 96% ee (Chiralcel OD-H, 25:75 i PrOH / hexanes, 1 mL / min, 254 nm), R t (major) = 26.2 min, R t (minor) = 37.5 min. IR (KBr thin film, cm -1 ): v 2905, 1608, 1504, 1442, 1243, 1220, 1098, 1036, 824, 702.

[0123] Example 9

[0124]

[0125] A mixture of formic acid and tetramethylethylenediamine (98 μL, n:n=5:2, 10.0 equiv) was dissolved in acetonitrile (1 mL), to the above solution was added aryl oxy substituted unsymmetrical diketone 1-1 (36.0 mg, 0.1 mmol) and Ru catalyst C4 (2.9 mg, 4 mol%), the reaction was stirred at 35 °C for 24 h. After the completion of the reaction was confirmed by TLC spotting, the reaction was extracted with ethyl acetate (3 x 5 mL), the obtained organic phase was dried over anhydrous sodium sulfate and then rotary evaporated to get the crude product. The obtained crude product was isolated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1, v / v). The obtained product sample was noted as 1-2, 15.3 mg in total, 42% yield, 99% ee, 70:17:8:5 dr.

[0126] Example 10

[0127]

[0128] A mixture of formic acid and tetramethylethylenediamine (98 μL, n:n=5:2, 10.0 equiv) was dissolved in acetonitrile (1 mL), to the above solution was added aryl oxy substituted unsymmetrical diketone 1-1 (36.0 mg, 0.1 mmol) and Ru catalyst C4 (2.9 mg, 4 mol%), the reaction was stirred at 35 °C for 24 h. After the completion of the reaction was confirmed by TLC spotting, the reaction was extracted with ethyl acetate (3 x 5 mL), the obtained organic phase was dried over anhydrous sodium sulfate and then rotary evaporated to get the crude product. The obtained crude product was isolated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1, v / v). The obtained product sample was noted as 1-2, 15.3 mg in total, 42% yield, 99% ee, 70:17:8:5 dr.

[0129] The above merely describes several embodiments of the present application, and does not limit the present application in any form. Although the present application is disclosed with the preferred embodiments, it is not intended to limit the present application. Any skilled person in the art can make some changes or modifications to the disclosed technical contents without departing from the scope of the technical solutions of the present application, and the equivalent embodiments are equivalent to the equivalent embodiments, which are within the scope of the technical solutions.

Claims

1. A process for the preparation of a chiral aryloxy-substituted chiral diol, characterized in that, The application relates to a method for preparing a chiral aryloxy-substituted chiral diol, comprising the following steps: a) preparing a chiral aryloxy-substituted chiral diol by selective transfer hydrogenation reaction of an aryloxy-substituted unsymmetrical diketone in the presence of a chiral catalyst and a transfer hydrogenation reagent; wherein the aryloxy-substituted unsymmetrical diketone has a structure shown in formula II: the chiral aryloxy-substituted chiral diol has a structure shown in formula I: wherein R 1 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl; R 2 selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl.

2. The method of claim 1, wherein, R 1 selected from C5-C 20 aryl, C5-C 20 substituted aryl, C4-C 20 heteroaryl, C4-C 20 substituted heteroaryl; R 2 selected from C1-C 20 alkyl, C1-C 20 substituted alkyl, C5-C 20 aryl, C5-C 20 substituted aryl, C4-C 20 heteroaryl, C4-C 20 substituted heteroaryl; Preferably, R 1 Selected from C5-C 10 Aryl, C5-C 10 Substituted aryl, C4-C 10 heteroaryl; R 2 selected from C1-C 10 alkyl, C1-C 10 substituted alkyl, C5-C 10 aryl, C5-C 10 substituted aryl, C4-C 10 heteroaryl.

3. The method of claim 1, wherein, each substituent in said substituted alkyl, substituted aryl or substituted heteroaryl is independently selected from the group consisting of C1-C 20 hydrocarbyl, C4-C 20 heteroaryl or a non-hydrocarbon group; Preferably, the non-hydrocarbon group is selected from oxygen, halogen, a group having a structure shown in formula (1), a group having a structure shown in formula (2) or a group having a structure shown in formula (3): wherein M 11 , M 21 and M 31 are independently selected from hydrogen or Ci-C 10 alkyl.

4. The method of claim 3, wherein, said non-hydrocarbon groups include oxygen, halogen, hydroxyl, C1-C 10 carboxyl, C1-C 10 ester, C1-C 10 alkoxy, C5-C 10 aryloxy and C1-C 10 acyloxy; Preferably, the halogen comprises F, Cl, Br and I.

5. The method of claim 1, wherein, The chiral catalyst is selected from a chiral metal complex-based catalyst; Preferably, the chiral catalyst is selected from at least one of the following catalysts C1-C11: Preferably, the molar ratio of the aryloxy-substituted unsymmetrical diketone to the chiral catalyst is 1:(0.02-0.06); Preferably, the molar ratio of the aryloxy-substituted unsymmetrical diketone to the chiral catalyst is 1:(0.03-0.05).

6. The method of claim 1, wherein, The transfer hydrogenation reagent is selected from at least one of the following: ammonium formate, sodium formate, isopropyl alcohol, formic acid / amine azeotrope; Preferably, the formic acid / amine azeotrope is selected from at least one of the following: formic acid / ethylamine, formic acid / n-propylamine, formic acid / i-propylamine, formic acid / n-butylamine, formic acid / t-butylamine, formic acid / dimethylamine, formic acid / diethylamine, formic acid / diisopropylamine, formic acid / tetramethylethylenediamine, formic acid / trimethylamine, formic acid / triethylamine; Preferably, the molar ratio of the transfer hydrogenation reagent to the aryloxy-substituted unsymmetrical diketone is (5-20):1; preferably (8-16):

1.

7. The method of claim 1, wherein, The reaction system further comprises a solvent selected from at least one of the following: acetonitrile, dichloromethane, dimethyl sulfoxide, ethyl acetate, isopropyl alcohol.

8. The method of claim 1, wherein, The reaction temperature of the reaction is 20-50 DEG C, and the reaction time is 15-35 h; Preferably, the reaction temperature of the reaction is 30-45 DEG C, and the reaction time is 20-30 h.

9. The method of claim 1, wherein, The method further comprises the step of separating and purifying the chiral aryloxy-substituted chiral diol.

10. The method according to any one of claims 1-9, characterized in that, The method comprises the following steps: a) placing a mixture containing the aryloxy-substituted unsymmetrical diketone, the transfer hydrogenation reagent and the chiral catalyst in a reaction container, stirring at 10-50 DEG C for 15-35 h to carry out the transfer hydrogenation reaction, and obtaining a reaction product; b) extracting the reaction product, and concentrating the obtained organic phase to obtain a chiral aryloxy-substituted chiral diol crude product; c) purifying the crude product by silica gel column chromatography to obtain a purified chiral aryloxy-substituted chiral diol.

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