Preparation method of chiral aryloxy substituted chiral alpha-hydroxy ketone

Abstract

The invention discloses a preparation method of chiral aryloxy substituted chiral alpha-hydroxy ketone, 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 alpha-hydroxy ketone. 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 alpha-hydroxy ketone 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 aryl-oxy-substituted chiral alpha-hydroxy ketone, and belongs to the field of chemical synthesis. BACKGROUND

[0002] Chiral dihydroxy ketone compounds are important skeletons of many natural products and drug molecules. For example, four kinds of polyphenol natural products rhuspolyphenol D, rhuspolyhenol E and rhuspolyhenol F have good anti-proliferation activity on four human tumor cell lines (A549, SK-OV-3, SK-MEL-2 and HCT-15). At the same time, rhuspolyhenol E can significantly inhibit the production of NO in mouse microglial BV-2 cells stimulated by lipopolysaccharide (LPS), and therefore has good anti-inflammatory activity.

[0003]

[0004] At present, there are few reports on the synthesis of dihydroxy ketones in the literature. Andrus et al. used phase transfer catalyst (PTC) to realize the asymmetric aldol reaction of enol silyl ether, and obtained cis-dihydroxy ketone with medium to high enantioselectivity, which is the only report on the asymmetric synthesis of cis-dihydroxy ketone so far, as shown in the following formula eq1. The asymmetric synthesis of trans-dihydroxy ketone has not been realized.

[0005] SUMMARY

[0006] In view of the above, the purpose of the present application is to provide a method for preparing a chiral aryl-oxy-substituted chiral alpha-hydroxy ketone. The method uses a chiral metal complex as a catalyst, and uses a non-chiral aryl-oxy-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 aryl-oxy-substituted chiral alpha-hydroxy ketone.

[0007] According to the present application, a method for preparing a chiral aryl-oxy-substituted chiral alpha-hydroxy ketone is provided, comprising:

[0008] In the presence of a chiral catalyst and a transfer hydrogenation reagent, the chiral aryl-oxy-substituted chiral alpha-hydroxy ketone is generated by selective transfer hydrogenation reaction from an aryl-oxy-substituted asymmetric diketone;

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

[0010]

[0011] The chiral aryloxy-substituted chiral α-hydroxy ketone has a structure shown in Formula I:

[0012]

[0013] Among them, R 1 is selected from hydrogen, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

[0014] R 2 is selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.

[0015] In some embodiments, R 1 Selected from hydrogen, C5-C 20 Aryl, C5-C 20 Substituted aryl, C4-C 20 Heteroaryl, C4-C 20 substituted heteroaryl;

[0016] 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.

[0017] In some embodiments, R 1 Selected from hydrogen, C5-C 10 Aryl, C5-C 10 Substituted aryl, C4-C 10 heteroaryl;

[0018] 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.

[0019] In some embodiments, the C1-C 10 The alkyl group of the alkyl group includes the C1-C 10 Straight chain alkyl, C3-C 10 Branched alkyl and C3-C 10 of a cycloalkyl group.

[0020] In the present application, Ar represents an aryl group or a substituted aryl group, which refers to any functional group or substituent derived from an aromatic ring or an aromatic ring containing a substituent. In some embodiments, Ar is selected from C5-C20 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 hydrocarbyl, C4-C 20 heteroaryl, or a non-hydrocarbyl group;

[0022] In some embodiments, the non-hydrocarbyl group is selected from oxygen, halogen, a group having the structure of Formula (1), a group having the structure of Formula (2), or a group having the structure of 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 C1-C 20 hydrocarbyl includes C1-C 20 alkyl, C2-C 20 alkenyl, C2-C 20 alkynyl, and C5-C 20 aryl.

[0026] In some embodiments, the non-hydrocarbyl group includes oxygen, halogen, hydroxyl, C1-C 10 carboxyl, C1-C 10 ester, C1-C 10 alkoxy, C5-C 10 aryloxy, and C1-C 10 acyloxy.

[0027] In some embodiments, the halogen includes F, Cl, Br, and I.

[0028] In some embodiments, the chiral catalyst is selected from a chiral metal complex-based catalyst.

[0029] In some embodiments, the chiral catalyst is selected from at least one of a chiral ruthenium (Ru) complex-based catalyst.

[0030] In some embodiments, the chiral catalyst is selected from at least one of the following catalysts C1-C11:

[0031]

[0032] In some embodiments, the molar ratio of the aryloxy-substituted asymmetric diketone to the chiral catalyst is 1:(0.005-0.035).

[0033] In some embodiments, the molar ratio of the aryloxy-substituted asymmetric diketone to the chiral catalyst is 1:(0.01-0.03).

[0034] In some embodiments, the molar ratio of the aryloxy-substituted asymmetric diketone to the chiral catalyst is independently selected from any value among 1:0.010, 1:0.011, 1:0.012, 1:0.013, 1:0.014, 1:0.015, 1:0.016, 1:0.017, 1:0.018, 1:0.019, 1:0.020, 1:0.021, 1:0.022, 1:0.023, 1:0.024, 1:0.025, 1:0.026, 1:0.027, 1:0.028, 1:0.029, 1:0.030, or any range therebetween.

[0035] In some embodiments, the transfer hydrogenation reagent is selected from at least one of ammonium formate, sodium formate, isopropyl alcohol, and formic acid / amine azeotrope.

[0036] 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 / tert-butylamine, formic acid / dimethylamine, formic acid / diethylamine, formic acid / diisopropylamine, formic acid / tetramethylethylenediamine, formic acid / trimethylamine, and formic acid / triethylamine.

[0037] In some embodiments, the transfer hydrogenation reagent is formic acid / tetramethylethylenediamine.

[0038] In some embodiments, the molar ratio of the transfer hydrogenation reagent to the aryloxy-substituted asymmetric diketone is (5-20):1.

[0039] In some embodiments, the molar ratio of the transfer hydrogenation reagent to the aryloxy-substituted unsymmetrical diketone is selected from any value 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, or any range therebetween.

[0040] In some embodiments, the molar ratio of the transfer hydrogenation reagent to the aryloxy-substituted asymmetric diketone is (8-16):1.

[0041] wherein the amine in the transfer hydrogenation reagent is used to assist the production of hydrogen source from formic acid, and the formic acid is used as the hydrogen source, and the molar ratio of the transfer hydrogenation reagent to the aryloxy-substituted unsymmetrical diketone is based on the amount of substance of the formic acid.

[0042] In some embodiments, the volume ratio of formic acid to amine in the formic acid / amine azeotrope is 5:2-6.

[0043] 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 5:2.0, 5:2.5, 5:3.0, 5:3.2, 5:3.5, 5:3.7, 5:4.0, 5:4.3, 5:4.5, 5:4.8, 5:5.0, 5:5.5, 5:6.0.

[0044] In some embodiments, the reaction system further comprises a solvent, which can be an additional solvent different from the starting material aryloxy-substituted unsymmetrical diketone and the transfer hydrogenation reagent.

[0045] In some embodiments, the solvent is selected from at least one of acetonitrile, dichloromethane, dimethyl sulfoxide, ethyl acetate, isopropanol.

[0046] In some embodiments, the selective transfer hydrogenation reaction of the aryloxy-substituted unsymmetrical diketone of the present application can occur without the need of additional solvent.

[0047] In some embodiments, the reaction temperature of the reaction is 5-40°C, and the reaction time is 1-10h.

[0048] In some embodiments, the reaction temperature of the reaction is independently selected from any value or a range between any two values selected from 10°C, 15°C, 20°C, 25°C, 30°C, 35°C.

[0049] In some embodiments, the reaction time of the reaction is independently selected from any value or a range between any two values selected from 3h, 4h, 5h, 6h, 7h, 8h.

[0050] In some preferred embodiments, the reaction temperature of the reaction is 10-35°C, and the reaction time is 3-8h. The inventors have found that the yield of the product can be improved at this reaction temperature and reaction time, and a higher reaction temperature or a longer reaction time can cause the generation of more other products.

[0051] In some embodiments, the method further comprises a step of isolating and purifying the chiral aryloxy-substituted chiral a-hydroxy ketone.

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

[0053] a) placing a mixture comprising the aryloxy-substituted asymmetric diketone, the transfer hydrogenation reagent, and the chiral catalyst in a reaction vessel, stirring at 5 to 40° C. for 1 to 10 hours 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 α-hydroxy ketone product;

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

[0056] In some embodiments, the extraction is performed using ethyl acetate.

[0057] In some embodiments, the concentrating comprises drying over anhydrous sodium sulfate and rotary evaporation.

[0058] In some embodiments, the concentrating is performed under reduced pressure.

[0059] The beneficial effects of this application include:

[0060] 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.

[0061] 2) The method provided in this application is to prepare a chiral aryloxy-substituted chiral α-hydroxyketone core skeleton with high selectivity through asymmetric transfer hydrogenation of aryloxy-substituted asymmetric diketone. The synthetic route is direct and atom economy is high. BRIEF DESCRIPTION OF THE DRAWINGS

[0062] Figure 1 The single crystal X-ray diffraction structure of the product sample 1-2 of Example 1 is shown.

[0063] Figure 2 The single crystal X-ray diffraction structure of sample 18-2, the product of Example 18, is shown. DETAILED DESCRIPTION

[0064] 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.

[0065] In this application, the expression "C1-C 10 ”, “C1-C 20 ” etc. refer to the number of carbon atoms contained in the group.

[0066] In the present application, the term "hydrocarbyl" refers to a group formed by removing any one hydrogen atom from a hydrocarbon compound, which includes alkane, alkene, alkyne and arene compounds, and the corresponding groups include alkyl, alkenyl, alkynyl and aryl groups; for example, p-tolyl formed by removing the hydrogen atom at the para position of the methyl group of toluene or benzyl formed by removing any one hydrogen atom from the methyl group of toluene.

[0067] In the present application, the term "alkyl" refers to a saturated hydrocarbyl group, which is formed by removing any one hydrogen atom from an alkane compound. In the present application, alkyl includes straight-chain alkyl, branched-chain alkyl and cyclic alkyl.

[0068] In the present application, the term "aryl" refers to a group formed by removing one hydrogen atom from an aromatic ring of an aromatic compound, for example, p-tolyl formed by removing the hydrogen atom at the para position of the methyl group of toluene.

[0069] In the present application, the term "heteroaryl" refers to a group formed by removing any one hydrogen atom from an aromatic ring of an aromatic compound containing O, N or S heteroatom in the aromatic ring, for example, furanyl formed by removing any one hydrogen atom from a furan ring.

[0070] In the present application, the term "halogen" refers to at least one of fluorine, chlorine, bromine and iodine.

[0071] In the present application, the term "non-hydrocarbyl group" refers to a group formed by removing any one hydrogen atom from a compound containing other elements (for example, halogen, S, O, P, N, etc.) other than H and C; some non-limiting examples include alkoxy, carboxyl, hydroxyl, ester, halogen, sulfonic acid, amino, nitro, etc.

[0072] In the present application, the term "alkoxy", usually represented by RO-, is composed of one alkyl group and one oxygen atom.

[0073] In the present application, the term "aryloxy" can be analogous to alkoxy, which is a group formed by connecting oxygen to an aromatic group, such as ph-O-.

[0074] 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 hydrocarbyl and heteroaryl groups themselves, not the number of carbon atoms after substitution. For example, "C1-C10 substituted alkyl" refers to an alkyl group with a carbon atom number of 1-10, in which at least one hydrogen atom is replaced by a substituent, such as a group with a carbon atom number of 11 formed by replacing one hydrogen atom of adamantyl with C≡N. 10

[0075] ​In this application, the term "substituted" includes substitution of at least one hydrogen atom, or substitution of two or more hydrogen atoms. The two or more hydrogen atoms may be hydrogen atoms on the same carbon atom or on different carbon atoms.

[0076] In this application, "transfer hydrogenation reagent" can also be used interchangeably with "hydrogen transfer reagent", "hydrogen atom transfer reagent", etc. in the art; it generally refers to a reagent used to introduce and / or remove hydrogen atoms, thereby changing the molecular structure and properties.

[0077] In this application, "chiral catalyst" refers to a compound with a chiral structure that can help control the stereoconfiguration of the product in a chemical reaction and improve the reaction selectivity and efficiency.

[0078] The present application is described in detail below with reference to embodiments, but the present application is not limited to these embodiments.

[0079] Unless otherwise specified, the raw materials and catalysts in the examples of this application were purchased from commercial sources.

[0080] The instruments used in the examples of this application are as follows:

[0081] 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.

[0082] The yield of the protected chiral aryloxy-substituted chiral α-hydroxy ketone is based on the amount of the aryloxy-substituted asymmetric diketone and is calculated by the following formula:

[0083] Yield % = (actual mass of target product obtained ÷ theoretical mass of target product) × 100%

[0084] 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; Et3N is triethylamine; 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.

[0085] In the description of the embodiments of the present application, the amount of catalyst is expressed in terms of mole percentage of the moles of catalyst relative to the moles of the aryloxy-substituted unsymmetrical diketone; the amount of the transfer hydrogenation reagent is expressed in terms of the molar equivalent of the transfer hydrogenation reagent relative to the aryloxy-substituted unsymmetrical diketone.

[0086] Example 1

[0087]

[0088] A mixture of formic acid and tetramethylethylenediamine (98 μL, n:n=5:2, 10.0 equiv) was dissolved in acetonitrile (1 mL), and the aryloxy-substituted unsymmetrical diketone 1-1 (34.6 mg, 0.1 mmol) and Ru catalyst C4 (1.1 mg, 1.5 mol%) were added to the above solution, which was stirred at 25 °C for 3 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 = 10:1, v / v). The obtained product sample was recorded as 1-2, 28.8 mg in total, with a yield of 83%, an ee value of 94%, a dr of 12:1, and a rr of 8:1.

[0089] The detection data of the product sample 1-2 are as follows:

[0090] White solid, mp 70-72 °C; 1 H NMR (400 MHz, CDC13) δ 7.89-7.86 (m, 2H), 7.63-7.59 (m, 1H), 7.48-7.45 (m, 2H), 7.26-7.23 (m, 3H), 7.22-7.18 (m, 2H), 6.69-6.63 (m, 4H), 5.53 (dd, J = 7.9, 4.2 Hz, 1H), 5.29 (d, J = 4.2 Hz, 1H), 3.68 (s, 3H), 3.67 (d, J = 6.0 Hz, 1H); 13 C NMR (101 MHz, CDC13) δ 199.5, 154.3, 151.6, 136.5, 135.2, 134.1, 129.0, 128.9, 128.5, 127.2, 117.2, 114.6, 83.0, 76.3, 55.7. HRMS (ESI-Quadrupole-Orbitrap) m / z: [M + Na] + Calcd for C 22 H 20 O4Na 317.1254; Found 317.1260. [a] D 26+16.9 (c 1.8, CHCl3); HPLC analysis: 94% ee (Chiralcel IC, 18:82 i PrOH / hexanes, 0.3 mL / min, 254 nm), R t (major) = 21.0 min, R t (minor) = 18.9 min. IR (KBr thin film, cm -1 ): v 2942, 2836, 1686, 1606, 1506, 1203, 1105, 1032, 829, 737.

[0091] The crystal structure of sample 1-2 was determined by X-ray single crystal diffractometer, and the results are shown in Figure 1 from which it can be determined that sample 1-2 is trans dihydroxy ketone. Figure 1

[0092] Example 2

[0093]

[0094] 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 (36.0 mg, 0.1 mmol) and Ru catalyst C4 (1.1 mg, 1.5 mol%) were added to the above solution, which was stirred at 25 °C for 3 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 = 10:1, v / v). The obtained product sample was recorded as 2-2, 33.0 mg in total, with a yield of 91%, an ee value of 90%, a dr of 12:1, and a rr of >20:1.

[0095] The detection data of product sample 2-2 are as follows:

[0096] yellow oily liquid; 1 H NMR (400 MHz, CDC13) δ 7.81 (d, J = 8.2 Hz, 2H), 7.29 - 7.24 (m, 5H), 7.20 - 7.18 (m, 2H), 6.68 (s, 4H), 5.52 (dd, J = 7.9, 4.1 Hz, 1H), 5.30 (d, J = 4.1 Hz, 1H), 3.68 (s, 3H), 3.67 (d, J = 7.5 Hz, 1H), 2.44 (s, 3H); 13 ​C NMR (101 MHz, CDC13) δ 198.8, 154.3, 151.6, 145.3, 136.4, 132.5, 129.7, 129.1, 128.42, 128.38, 127.3, 117.3, 114.6, 83.0, 76.1, 55.7, 22.0. HRMS (ESI-Quadrupole-Orbitrap) m / z: [M + Na] + Calcd for C 23 H 22 O4Na 385.1410; Found 385.1415. [a] D 26 +47.2 (c 1.1, CHCl3); HPLC analysis: 90% ee (Chiralcel IC, 18:82 i PrOH / hexanes, 0.3 mL / min, 254 nm), R t (major) = 26.7 min, R t (minor) = 21.8 min. IR (KBr thin film, cm -1 ): v 2924, 2838, 1678, 1606, 1499, 1453, 1213, 1107, 1033, 823, 733.

[0097] Example 3

[0098]

[0099] 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 3-1 (43.6 mg, 0.1 mmol) and Ru catalyst C4 (1.1 mg, 1.5 mol%) were added to the above solution, which was stirred at 25 °C for 3 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 = 10:1, v / v). The obtained product sample was recorded as 3-2, 36.0 mg in total, with a yield of 82%, ee value of 96%, 11:1 dr, 11:1 rr.

[0100] The detection data of product sample 3-2 are as follows:

[0101] White solid, mp 104-106 °C; 1H NMR (400 MHz, CDC13) δ 7.26 - 7.25 (m, 3H), 7.21 - 7.18 (m, 2H), 7.04 (s, 2H), 6.74 - 6.68 (m, 4H), 5.44 (dd, J = 8.1, 3.8 Hz, 1H), 5.35 (d, J = 3.8 Hz, 1H), 3.93 (s, 3H), 3.82 (s, 6H), 3.74 (d, J = 8.2 Hz, 1H), 3.69 (s, 3H); 13 C NMR (101 MHz, CDC13) δ 198.0, 154.5, 153.1, 151.7, 143.3, 136.6, 130.2, 128.4, 127.2, 117.6, 114.6, 106.3, 83.8, 76.2, 61.2, 56.4, 55.7. HRMS (ESI-Quadrupole-Orbitrap) m / z: [M+Na] + Calcd for C 25 H 26 O7Na 461.1571; Found 461.1571. [a] D 26 +31.1 (c 0.8, CHCl3); HPLC analysis: 96% ee (Chiralcel IA, 20:80 i PrOH / hexanes, 1 mL / min, 254 nm), R t (major) = 15.0 min, R t (minor) = 9.0 min. IR (KBr thin film, cm -1 ): v 2939, 2835, 1672, 1583, 1502, 1416, 1331, 1223, 1126, 832, 734.

[0102] Example 4

[0103]

[0104] 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 4-1 (36.4 mg, 0.1 mmol) and Ru catalyst C4 (1.1 mg, 1.5 mol%) were added to the above solution, which was stirred at 25 °C for 3 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 = 10:1, v / v). The obtained product sample was recorded as 4-2, 31.0 mg in total, with a yield of 85%, an ee value of 93%, a 13:1 dr, and a 9:1 rr.

[0105] The detection data of product sample 4-2 are as follows:

[0106] White solid, mp 92-94 °C; 1 H NMR (400 MHz, CDCl3) δ 7.92-7.87 (m, 2H), 7.29-7.26 (m, 3H), 7.25-7.21 (m, 2H), 7.14-7.08 (m, 2H), 6.69-6.61 (m, 4H), 5.43 (dd, J = 8.1, 4.7 Hz, 1H), 5.24 (d, J = 4.7 Hz, 1H), 3.71 (d, J = 8.4 Hz, 1H), 3.68 (s, 3H); 19 F NMR (376 MHz, CDCl3) δ -103.05; 13 C NMR (101 MHz, CDCl3) δ 198.1, 166.3 (C-F, d, 1 J C-F = 256.8 Hz), 154.4, 151.5, 136.7, 131.8, 131.7 (C-F, d, 3 J C-F = 3.2 Hz), 128.6, 128.5, 127.1, 117.1, 116.0 (C-F, d, 2 J C-F = 22.0 Hz), 114.6, 83.2, 76.1, 55.7. HRMS (ESI-Quadrupole-Orbitrap) m / z: [M + Na] + Calcd for C 22 H 19 O4FNa 389.1160; Found 389.1164. [a] D 26+31.2 (c 2.1, CHCI3); HPLC analysis: 93% ee (Chiralcel IC, 30:70 i PrOH / hexanes, 0.5 mL / min, 254 nm), R t (major) = 18.4 min, R t (minor) = 20.1 min. IR (KBr thin film, cm -1 ): v 2932, 2835, 1631, 1497, 1454, 1158, 1036, 825, 734.

[0107] Example 5

[0108]

[0109] A mixture of formic acid and tetramethylethylenediamine (98 μί, n:n=5:2, 10.0 equiv) was dissolved in acetonitrile (1 mL), and arlyoxy-substituted unsymmetrical diketone 5-1 (35.2 mg, 0.1 mmol) and Ru catalyst C4 (1.1 mg, 1.5 mol%) were added to the above solution, which was stirred at 25 °C for 3 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 = 10:1, v / v). The obtained product sample was noted as 5-2, 33.3 mg in total, with a yield of 94%, an ee value of 87%, a dr of 14:1, and a rr of >20:1.

[0110] The detection data of product sample 5-2 are as follows:

[0111] colorless oily liquid; 1 H NMR (400 MHz, CDC13) δ 7.73 (d, J = 4.9 Hz, 1H), 7.65 (d, J = 3.3 Hz, 1H), 7.30 - 7.26 (m, 5H), 7.12 - 7.10 (m, 1H), 6.69 (s, 4H), 5.31 (d, J = 4.8 Hz, 1H), 5.26 (dd, J = 8.3, 4.8 Hz, 1H), 3.68 (s, 3H), 3.55 (d, J = 8.3 Hz, 1H); 13 C NMR (101 MHz, CDC13) δ 191.6, 154.4, 151.6, 141.5, 136.7, 135.4, 134.1, 128.6, 128.5, 127.3, 117.3, 114.6, 83.4, 77.2, 55.7.[α] D26 +10.2 (c 0.7, CHCl3); HPLC analysis: 87% ee (Chiralcel IC, 7:93 i PrOH / hexanes, 1 mL / min, 254 nm), R t (major) = 17.4 min, R t (minor) = 15.9 min. HRMS (ESI-Quadrupole-Orbitrap) m / z: [M+Na] + Calcd for C 20 H 18 O4SNa 371.0818; Found 371.0818. IR (KBr thin film, cm -1 ): v 2932, 2836, 1658, 1506, 1454, 1416, 1264, 1224, 1039, 826, 734.

[0112] Example 6

[0113]

[0114] 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 6-1 (39.0 mg, 0.1 mmol) and Ru catalyst C4 (1.1 mg, 1.5 mol%), the reaction was stirred at 25 °C for 3 h. After the reaction was confirmed to be completed 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 = 10:1, v / v). The obtained product sample was noted as 6-2, 31.5 mg in total, 80% yield, 94% ee, 9:1 dr, 7:1 rr.

[0115] The detection data of product sample 6-2 were as follows:

[0116] colorless oily liquid; 1H NMR (400 MHz, CDC13) δ 7.90 (d, J = 7.3 Hz, 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.49 (t, J = 7.7 Hz, 2H), 6.76 - 6.74 (m, 1H), 6.69 - 6.64 (m, 5H), 6.62 - 6.57 (m, 1H), 5.91 (s, 2H), 5.49 (dd, J = 7.9, 4.3 Hz, 1H), 5.19 (d, J = 4.3 Hz, 1H), 3.69 (s, 3H), 3.66 (d, J = 1.5 Hz, 1H); 13 C NMR (101 MHz, CDC13) δ 199.5, 154.3, 151.4, 147.9, 147.7, 135.1, 134.2, 130.2, 129.0, 120.8, 117.2, 114.6, 108.1, 107.8, 101.2, 82.5, 76.2, 55.7. HRMS (ESI-Quadrupole-Orbitrap) m / z: [M+Na] + Calcd for C 23 H 20 O6Na 415.1152; Found 415.1149. [a] D 26 +19.6 (c 1.2, CHCl3); HPLC analysis: 94% ee (Chiralcel OJ-H, 20:80 i PrOH / hexanes, 1 mL / min, 254 nm), R t (major) = 20.6 min, R t (minor) = 16.5 min. IR (KBr thin film, cm -1 ): v 2905, 2836, 1682, 1597, 1505, 1444, 1264, 1222, 1037, 825, 732.

[0117] Example 7

[0118]

[0119] 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 7-1 (45.2 mg, 0.1 mmol) and Ru catalyst C4 (1.1 mg, 1.5 mol%) were added to the above solution, which was stirred at 25 °C for 3 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 = 10:1, v / v). The obtained product sample was recorded as 7-2, 36.3 mg in total, with a yield of 80%, an ee value of 92%, a 5:1 dr, and a 6:1 rr.

[0120] The detection data of product sample 7-2 are as follows:

[0121] colorless oily liquid; 1 H NMR (600 MHz, CDC13) δ 7.89 (d, J = 7.3 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.8 Hz, 2H), 7.43-7.36 (m, 4H), 7.35-7.32 (m, 1H), 7.12 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 6.68-6.65 (m, 4H), 5.51 (dd, J = 7.8, 4.3 Hz, 1H), 5.25 (d, J = 4.3 Hz, 1H), 5.01 (s, 2H), 3.68 (s, 3H), 3.66 (d, J = 6.7 Hz, 1H); 13 C NMR (101 MHz, CDC13) δ 199.6, 158.9, 154.3, 151.6, 137.0, 135.2, 134.1, 129.0, 128.9, 128.7, 128.7, 128.5, 128.2, 127.6, 117.3, 114.8, 114.6, 82.6, 76.3, 70.1, 55.7. HRMS (ESI-Quadrupole-Orbitrap) m / z: [M+Na] + Calcd for C 29 H 26 O5Na 477.1672; Found 477.1679. [a] D 26 +18.3 (c 0.9, CHCl3); HPLC analysis: 92% ee (Chiralcel IC, 10:90 iR = 18.0 min, R t (major) = 18.0 min, R t (minor) = 15.7 min. IR (KBr thin film, cm -1 ): v 2933, 2836, 1681, 1609, 1505, 1453, 1264, 1214, 1173, 1034, 825, 737.

[0122] Example 8

[0123]

[0124] 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 8-1 (35.2 mg, 0.1 mmol) and Ru catalyst C4 (1.1 mg, 1.5 mol%) were added to the above solution, and the reaction was stirred at 25 °C for 3 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 a crude product. The obtained crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, v / v). The obtained product sample was designated as 8-2, and the yield was 26.5 mg, 75%, with an ee value of 93%, 7:1 dr, and 6:1 rr.

[0125] The detection data of product sample 8-2 are as follows:

[0126] colorless oily liquid; 1 H NMR (400 MHz, CDC13) δ 7.85 (d, J = 7.3 Hz, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.7 Hz, 2H), 7.23 (dd, J = 4.9, 3.0 Hz, 1H), 7.03 (d, J = 2.5 Hz, 1H), 6.95 (d, J = 4.2 Hz, 1H), 6.70 (s, 4H), 5.52 (dd, J = 7.6, 4.0 Hz, 1H), 5.42 (d, J = 3.9 Hz, 1H), 3.76 (d, J = 7.7 Hz, 1H), 3.70 (s, 3H); 13C NMR (101 MHz, CDC13) δ 199.3, 154.5, 151.7, 137.7, 135.1, 134.2, 129.0, 128.9, 126.4, 126.1, 123.3, 117.4, 114.6, 80.1, 75.9, 55.7. HRMS (ESI-Quadrupole-Orbitrap) m / z: [M + Na] + Calcd for C 20 H 18 O4SNa 377.0818; Found 377.0822. [a] D 26 + 25.8 (c 0.9, CHCl3); HPLC analysis: 93% ee (Chiralcel IC, 7:93 i PrOH / hexanes, 1 mL / min, 254 nm), R t (major) = 13.1 min, R t (minor) = 12.2 min. IR (KBr thin film, cm -1 ): v 3108, 2930, 2835, 1731, 1682, 1597, 1507, 1449, 1223, 1181, 1035, 826, 737.

[0127] Example 9

[0128]

[0129] 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 9-1 (37.4 mg, 0.1 mmol) and Ru catalyst C4 (1.1 mg, 1.5 mol%) were added to the above solution, and the reaction was stirred at 25 °C for 3 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 = 10:1, v / v). The obtained product sample was noted as 9-2, 32.0 mg in total, with a yield of 85%, ee value of 98%, >20:1 dr, >20:1 rr.

[0130] The detection data of product sample 9-2 are as follows:

[0131] colorless oily liquid; 11H NMR (600 MHz, CDCl3) δ 7.35 - 7.30 (m, 5H), 7.25 - 7.23 (m, 2H), 7.20 - 7.16 (m, 1H), 7.09 - 7.07 (m, 2H), 6.76 - 6.71 (m, 4H), 5.22 (d, J = 4.9 Hz, 1H), 4.55 (dd, J = 6.3, 5.0 Hz, 1H), 3.71 (s, 3H), 3.46 (d, J = 6.4 Hz, 1H), 2.90 - 2.83 (m, 3H), 2.63 - 2.57 (m, 1H); 13 13C NMR (101 MHz, CDCl3) δ 209.3, 154.5, 151.4, 140.6, 137.0, 128.7, 128.6, 128.5, 128.4, 126.9, 126.3, 117.1, 114.7, 82.4, 79.9, 55.7, 42.4, 29.3. HRMS (ESI - Quadrupole - Orbitrap) m / z: [M + Na] + Calcd for C 24 H 24 O4Na 399.1567; Found 399.1572. [α] D 22 : +57.2 (c 0.20, CHCl3); HPLC analysis: 98% ee (Chiralcel IC, 10:90 i PrOH / hexanes, 1 mL / min, 254 nm), R t (major) = 6.7 min, R t (minor) = 9.8 min. IR (KBr thin film, cm -1 ): ν 3735, 3004, 2970, 2360, 1738, 1715, 1364, 1218, 1091, 900, 528.

[0132] Example 10

[0133]

[0134] 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 10-1 (40.8 mg, 0.1 mmol) and Ru catalyst C4 (1.1 mg, 1.5 mol%) were added to the above solution, which was stirred at 25 °C for 3 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 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 = 10:1, v / v). The obtained product sample was noted as 10-2, 38.3 mg in total, with a yield of 93%, ee value of 97%, >20:1 dr, >20:1 rr.

[0135] The detection data of product sample 10-2 are as follows:

[0136] colorless oily liquid; 1 H NMR (400 MHz, CDC13) δ 7.40-7.34 (m, 4H), 7.33-7.28 (m, 1H), 6.79-6.71 (m, 4H), 5.86-5.74 (m, 1H), 5.23 (d, J = 4.9 Hz, 1H), 5.03-4.96 (m, 1H), 4.95-4.91 (m, 1H), 4.57 (dd, J = 6.2, 4.9 Hz, 1H), 3.71 (s, 3H), 3.56 (d, J = 6.4 Hz, 1H), 2.55-2.47 (m, 1H), 2.32-2.24 (m, 1H), 2.06-2.00 (m, 2H), 1.57-1.50 (m, 2H), 1.37-1.31 (m, 2H), 1.28-1.18 (m, 8H); 13 C NMR (101 MHz, CDC13) δ 210.3, 154.4, 151.6, 139.3, 137.2, 128.7, 128.5, 127.0, 117.1, 114.7, 114.3, 82.5, 79.8, 55.7, 40.9, 33.9, 29.36, 29.35, 29.2, 29.0, 23.4. HRMS (ESI-Quadrupole-Orbitrap) m / z: [M + Na] + Calcd for C 26 H 34 O4Na 433.2349; Found 433.2347. [a] D 22 +27.6 (c 0.6, CHCl3); HPLC analysis: 97% ee (Chiralcel IC, 4:96i PrOH / hexanes, 1 mL / min, 254 nm), R t (major) = 8.0 min, R t (minor) = 7.2 min. IR (KBr thin film, cm -1 ): v 2932, 2831, 1714, 1601, 1505, 1453, 1265, 1223, 1181, 1026, 825, 698.

[0137] Example 11

[0138]

[0139] 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 11-1 (31.0 mg, 0.1 mmol) and Ru catalyst C4 (1.1 mg, 1.5 mol%) were added to the above solution, and the reaction was stirred at 25 °C for 3 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 = 10:1, v / v). The obtained product sample was designated as 11-2, 29.3 mg in total, with a yield of 94%, an ee value of 93%, a 6:1 dr, and a >20:1 rr.

[0140] The detection data of product sample 11-2 are as follows:

[0141] White solid, mp 42-44 °C; 1 H NMR (400 MHz, CDC13) δ 7.43-7.41 (m, 2H), 7.37-7.32 (m, 2H), 7.31-7.28 (m, 1H), 6.81-6.77 (m, 2H), 6.75-6.72 (m, 2H), 5.34 (d, J = 4.3 Hz, 1H), 4.83-4.80 (m, 1H), 3.71 (s, 3H), 3.68 (br, 1H), 1.87-1.81 (m, 1H), 1.19-1.14 (m, 2H), 0.99-0.94 (m, 2H); 13C NMR (101 MHz, CDC13) δ 209.5, 154.4, 151.9, 137.1, 128.6, 128.4, 127.1, 117.3, 114.7, 82.6, 80.7, 55.7, 19.4, 13.4, 13.1. HRMS (ESI-Quadrupole-Orbitrap) m / z: [M + Na] + Calcd for C 19 H 20 O4Na 335.1254; Found 335.1258. [a] D 26 + 28.1 (c 3.2, CHCl3); HPLC analysis: 93% ee (Chiralcel IC, 7:93 i PrOH / hexanes, 1 mL / min, 254 nm), R t (major) = 11.1 min, R t (minor) = 13.5 min. IR (KBr thin film, cm -1 ): v 3007, 2836, 1693, 1505, 1453, 1375, 1264, 1215, 1023, 824, 699.

[0142] Example 12

[0143]

[0144] 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 12-1 (32.6 mg, 0.1 mmol) and Ru catalyst C4 (1.1 mg, 1.5 mol%) were added to the above solution, which was stirred at 25 °C for 3 h. After the reaction was confirmed to be completed 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 = 10:1, v / v). The obtained product sample was recorded as 12-2, 29.5 mg in total, with a yield of 90%, an ee value of 97%, a dr of 17:1, and a rr of 20:1.

[0145] The detection data of product sample 12-2 are as follows:

[0146] White solid, mp 49-51 °C; 1H NMR (600 MHz, CDC13) δ 7.39 - 7.34 (m, 4 H), 7.33 - 7.29 (m, 1 H), 6.79 - 6.76 (m, 2 H), 6.74 - 6.71 (m, 2 H), 5.21 (d, J = 4.9 Hz, 1 H), 4.54 (dd, J = 6.2, 5.1 Hz, 1 H), 3.71 (s, 3 H), 3.55 (d, J = 6.5 Hz, 1 H), 2.41 (dd, J = 16.9, 7.1 Hz, 1 H), 2.24 (dd, J = 16.9, 6.6 Hz, 1 H), 2.12 (dt, J = 13.4, 6.7 Hz, 1 H), 0.86 (d, J = 6.7 Hz, 3 H), 0.84 (d, J = 6.6 Hz, 3 H); 13 CNMR (151 MHz, CDC13) δ 209.9, 154.4, 151.5, 137.2, 128.7, 128.5, 127.1, 117.1, 114.7, 82.5, 79.9, 55.7, 49.8, 24.5, 22.7, 22.6. HRMS (ESI-Quadrupole-Orbitrap) m / z: [M + Na] + Calcd for C 20 H 24 O4Na 351.1567; Found 351.1567. [a] D 26 +81.4 (c 0.6, CHCl3); HPLC analysis: 97% ee (Chiralcel IA, 10:90 i PrOH / hexanes, 1 mL / min, 254 nm), R t (major) = 6.4 min, R t (minor) = 7.1 min. IR (KBr thin film, cm -1 ): v 2956, 2871, 1711, 1504, 1454, 1223, 1180, 1036, 824, 701.

[0147] Example 13

[0148]

[0149] A mixture of formic acid and tetramethylethylenediamine (158 μL, n:n=5:4, 10.0 equiv) was dissolved in acetonitrile (1 mL), and aryloxy-substituted unsymmetrical diketone 13-1 (37.4 mg, 0.1 mmol) and Ru catalyst C2 (1.0 mg, 1.5 mol%) were added to the above solution, which was stirred at 25 °C for 8 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 = 10:1, v / v). The resulting product sample was noted as 13-2, 32.7 mg in total, with a yield of 87%, an ee value of 97%, and a 89:11:0:0 dr.

[0150] The detection data of product sample 13-2 are as follows:

[0151] colorless oily liquid; 1 H NMR (400 MHz, CDC13) δ 7.40-7.33 (m, 5H), 7.25-7.19 (m, 3H), 6.92-6.90 (m, 2H), 6.79-6.72 (m, 4H), 5.22 (d, J = 4.8 Hz, 1H), 4.53 (dd, J = 7.4, 4.8 Hz, 1H), 3.80 (q, J = 6.8 Hz, 1H), 3.72 (s, 3H), 3.56 (d, J = 7.4 Hz, 1H), 1.38 (d, J = 6.9 Hz, 3H); 13 C NMR (101 MHz, CDC13) δ 209.7, 154.5, 151.8, 139.3, 137.7, 129.2, 128.9, 128.5, 128.2, 127.5, 126.7, 117.2, 114.7, 83.4, 78.1, 55.8, 51.1, 17.3. HRMS (ESI-Quadrupole-Orbitrap) m / z: [M + Na] + Calcd for C 24 H 24 O4Na 399.1567; Found 399.1569. [a] D 27 +93.7 (c 2.5, CHCl3); HPLC analysis: 97% ee (Chiralcel IA, 7:93 i PrOH / hexanes, 1 mL / min, 254 nm), R t (major) = 10.1 min, R t(minor) = 13.8 min. IR (KBr thin film, cm -1 ): v 3019, 2833, 1714, 1506, 1453, 1214, 1039, 754, 700.

[0152] Example 14

[0153]

[0154] A mixture of formic acid and tetramethylethylenediamine (158 μL, n:n = 5:4, 10.0 equiv) was dissolved in acetonitrile (1 mL), and aryloxy-substituted unsymmetrical diketone 14-1 (45.0 mg, 0.1 mmol) and Ru catalyst C2 (1.0 mg, 1.5 mol%) were added to the above solution, and the reaction was stirred at 25 °C for 8 h. After confirming the completion of the reaction 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 a crude product. The obtained crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, v / v). The obtained product sample was designated as 14-2, and the yield was 40.2 mg, 89%, with an ee value of 97% and a dr of 83:17:0:0.

[0155] The detection data of product sample 14-2 are as follows:

[0156] colorless oily liquid; 1 H NMR (400 MHz, CDC13) δ 7.36 - 7.31 (m, 3 H), 7.22 - 7.19 (m, 5 H), 7.16 - 7.11 (m, 3 H), 6.99 - 6.96 (m, 2 H), 6.83 - 6.81 (m, 2 H), 6.74 - 6.70 (m, 2 H), 6.68 - 6.63 (m, 2 H), 5.15 (d, J = 4.5 Hz, 1 H), 4.48 (dd, J = 7.2, 4.5 Hz, 1 H), 4.00 (t, J = 7.3 Hz, 1 H), 3.72 (s, 3 H), 3.58 (d, J = 7.3 Hz, 1 H), 3.43 (dd, J = 13.7, 7.4 Hz, 1 H), 2.89 (dd, J = 13.7, 7.2 Hz, 1 H); 13C NMR (101 MHz, CDC13) δ 208.3, 154.4, 151.7, 139.3, 137.4, 137.1, 129.4, 129.1, 128.9, 128.7, 128.4, 128.3, 127.7, 126.8, 126.3, 117.1, 114.6, 82.9, 78.3, 58.7, 55.8, 38.1. HRMS (ESI-Quadrupole-Orbitrap) m / z: [M + Na] + Calcd for C 30 H 28 O4Na 475.1880; Found 475.1884. [a] D 27 +61.8 (c 2.0, CHCl3); HPLC analysis: 97% ee (Chiralcel IA, 7:93 i PrOH / hexanes, 1 mL / min, 254 nm), R t (major) = 16.7 min, R t (minor) = 12.3 min. IR (KBr thin film, cm -1 ): v 3028, 2924, 1712, 1601, 1505, 1453, 1265, 1222, 1030, 824, 692.

[0157] Example 15

[0158]

[0159] A mixture of formic acid and tetramethylethylenediamine (158 μL, n:n = 5:4, 10.0 equiv) was dissolved in acetonitrile (1 mL), and aryloxy-substituted unsymmetrical diketone 15-1 (41.2 mg, 0.1 mmol) and Ru catalyst C2 (1.0 mg, 1.5 mol%) were added to the above solution, which was stirred at 25 °C for 8 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 = 10:1, v / v). The obtained product sample was noted as 15-2, 33.5 mg in total, with a yield of 81%, an ee value of 97%, and a 86:14:0:0 dr.

[0160] The detection data of product sample 15-2 are as follows:

[0161] colorless oily liquid; 1H NMR (400 MHz, CDC13) δ 7.41 - 7.32 (m, 5 H), 7.26 - 7.23 (m, 3 H), 6.94 - 6.92 (m, 2 H), 6.81 - 6.77 (m, 2 H), 6.75 - 6.72 (m, 2 H), 5.22 (d, J = 5.1 Hz, 1 H), 4.49 (dd, J = 7.2, 5.2 Hz, 1 H), 4.06 (t, J = 7.3 Hz, 1 H), 3.71 (s, 3 H), 3.46 (d, J = 7.4 Hz, 1 H), 2.88 (ddd, J = 16.6, 7.8, 2.5 Hz, 1 H), 2.46 (ddd, J = 16.6, 6.7, 2.6 Hz, 1 H), 1.62 (t, J = 2.5 Hz, 3 H); 13 CNMR (101 MHz, CDC13) δ 208.2, 154.4, 151.6, 137.5, 136.5, 129.2, 128.9, 128.5, 128.0, 127.0, 117.2, 114.7, 83.0, 78.0, 76.6, 56.4, 55.8, 22.0, 3.6. HRMS (ESI-Quadrupole-Orbitrap) m / z: [M + Na] + Calcd for C 27 H 26 O4Na 437.1723; Found 437.1729. [a] D 27 +82.6 (c 1.6, CHCl3); HPLC analysis: 97% ee (Chiralcel IA, 7:93 i PrOH / hexanes, 1 mL / min, 254 nm), R t (major) = 12.7 min, R t (minor) = 14.1 min. IR (KBr thin film, cm -1 ): v 3019, 2836, 1715, 1506, 1454, 1214, 1039, 826, 700.

[0162] Example 16

[0163]

[0164] A mixture of formic acid and tetramethylethylenediamine (158 μL, n:n = 5:4, 10.0 equiv) was dissolved in acetonitrile (1 mL), and aryloxy-substituted unsymmetrical diketone 16-1 (43.2 mg, 0.1 mmol) and Ru catalyst C2 (1.0 mg, 1.5 mol%) were added to the above solution, which was stirred at 25 °C for 8 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 = 10:1, v / v). The resulting product sample was noted as 16-2, 37.0 mg in total, with a yield of 85%, an ee value of 96%, and a 74:22:4:0 dr.

[0165] The detection data of product sample 16-2 are as follows:

[0166] colorless oily liquid; 1 H NMR (400 MHz, CDC13) δ 7.39 - 7.29 (m, 5H), 7.25 - 7.23 (m, 3H), 6.96 - 6.94 (m, 2H), 6.82 - 6.77 (m, 2H), 6.74 - 6.70 (m, 2H), 5.26 (d, J = 5.5 Hz, 1H), 4.54 - 4.49 (m, 2H), 3.71 (s, 3H), 3.59 (s, 3H), 3.44 (d, J = 7.0 Hz, 1H), 3.18 (dd, J = 16.8, 8.8 Hz, 1H), 2.62 (dd, J = 16.8, 5.9 Hz, 1H); 13 C NMR (101 MHz, CDC13) δ 208.2, 172.1, 154.4, 151.5, 137.3, 136.4, 129.4, 128.8, 128.6, 128.5, 128.0, 127.3, 117.3, 114.7, 82.4, 77.8, 77.4, 55.8, 52.0, 36.9. HRMS (ESI-Quadrupole-Orbitrap) m / z: [M + Na] + Calcd for C 26 H 26 O6Na 457.1622; Found 457.1662. [a] D 27 +47.9 (c 2.6, CHCl3); HPLC analysis: 96% ee (Chiralcel IC, 10:90 i PrOH / hexanes, 1 mL / min, 254 nm), R t(major) = 9.2 min, R t (minor) = 11.0 min. IR (KBr thin film, cm -1 ): v 2984, 2905, 1739, 1447, 1372, 1238, 1043, 938, 634.

[0167] Example 17

[0168]

[0169] A mixture of formic acid and tetramethylethylenediamine (158 μL, n:n = 5:4, 10.0 equiv) was dissolved in acetonitrile (1 mL), and aryloxy-substituted unsymmetrical diketone 17-1 (40.0 mg, 0.1 mmol) and Ru catalyst C2 (1.0 mg, 1.5 mol%) were added to the above solution, and the reaction was stirred at 25 °C for 8 h. After confirming the completion of the reaction 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 a crude product. The obtained crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, v / v). The obtained product sample was designated as 17-2, and the yield was 33.0 mg, 82%, with an ee value of 98% and a dr of 83:11:6:0.

[0170] The detection data of product sample 17-2 are as follows:

[0171] colorless oily liquid; 1 H NMR (600 MHz, CDC13) δ 7.40-7.38 (m, 4H), 7.37-7.33 (m, 1H), 7.25-7.21 (m, 3H), 6.88-6.86 (m, 2H), 6.79-6.77 (m, 2H), 6.75-6.73 (m, 2H), 5.59-5.21 (m, 1H), 5.24 (d, J = 4.7 Hz, 1H), 4.98-4.94 (m, 1H), 4.91-4.90 (m, 1H), 4.49 (dd, J = 7.2, 4.6 Hz, 1H), 3.76 (t, J = 7.4 Hz, 1H), 3.72 (s, 3H), 3.60 (d, J = 7.3 Hz, 1H), 2.81-2.76 (m, 1H), 2.46-2.41 (m, 1H); 13C NMR (151 MHz, CDC13) δ 208.6, 154.5, 151.7, 137.6, 137.0, 135.5, 129.1, 128.9, 128.7, 128.5, 127.7, 126.8, 117.1, 117.0, 114.7, 83.3, 78.3, 56.7, 55.8, 36.1. HRMS (ESI-Quadrupole-Orbitrap) m / z: [M + Na] + Calcd for C 26 H 26 O4Na 425.1723; Found 425.1721. [a] D 27 + 50.0 (c 2.2, CHCl3); HPLC analysis: 98% ee (Chiralcel OJ-H, 2:98 i PrOH / hexanes, 1 mL / min, 254 nm), R t (major) = 16.4 min, R t (minor) = 22.7 min. IR (KBr thin film, cm -1 ): v 3057, 2833, 1714, 1598, 1505, 1454, 1264, 1223, 1038, 825, 742.

[0172] Example 18

[0173]

[0174] A mixture of formic acid and tetramethylethylenediamine (158 μL, n:n = 5:4, 10.0 equiv) was dissolved in acetonitrile (1 mL), and arlyoxy-substituted unsymmetrical diketone 18-1 (40.4 mg, 0.1 mmol) and Ru catalyst C2 (1.0 mg, 1.5 mol%) were added to the above solution, which was stirred at 25 °C for 8 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 = 10:1, v / v). The obtained product sample was noted as 18-2, 32.9 mg in total, with a yield of 81%, an ee value of 96%, and a 88:10:2:0 dr.

[0175] The detection data of product sample 18-2 are as follows:

[0176] White solid, mp 91-93 °C; 1H NMR (400 MHz, CDC13) δ 7.30 - 7.26 (m, 3 H), 7.25 - 7.19 (m, 2 H), 7.00 - 6.98 (m, 2 H), 6.92 - 6.88 (m, 2 H), 6.80 - 6.70 (m, 4 H), 5.15 (d, J = 5.0 Hz, 1 H), 4.51 (dd, J = 7.4, 5.1 Hz, 1 H), 3.89 (q, J = 6.9 Hz, 1 H), 3.81 (s, 3 H), 3.72 (s, 3 H), 3.45 (d, J = 7.4 Hz, 1 H), 1.38 (d, J = 6.9 Hz, 3 H); 13 C NMR (101 MHz, CDC13) δ 210.1, 159.7, 154.5, 151.7, 139.4, 129.5, 129.2, 128.2, 128.1, 127.5, 117.3, 114.7, 114.3, 82.9, 77.9, 55.8, 55.4, 51.1, 17.4. HRMS (ESI-Quadrupole-Orbitrap) m / z: [M + Na] + Calcd for C 25 H 26 O5Na 429.1472; Found 429.1471. [a] D 27 +58.1 (c 1.1, CHCl3); HPLC analysis: 96% ee (Chiralcel IC, 5:95 i PrOH / hexanes, 1 mL / min, 254 nm), R t (major) = 15.1 min, R t (minor) = 10.9 min. IR (KBr thin film, cm -1 ): v 2934, 2836, 1713, 1611, 1505, 1453, 1223, 1174, 1031, 824, 700.

[0177] The crystal structure of sample 18-2 was determined by X-ray single crystal diffractometer, and the results are shown in Figure 2 from which it can be determined that sample 18-2 is a trans dihydroxy ketone. Figure 2 Example 19

[0178]

[0179]

[0180] ​A mixture of formic acid and tetramethylethylenediamine (158 μL, n:n = 5:4, 10.0 equiv) was dissolved in acetonitrile (1 mL), and aryloxy-substituted unsymmetrical diketone 19-1 (46.4 mg, 0.1 mmol) and Ru catalyst C2 (1.0 mg, 1.5 mol%) were added to the above solution, which was stirred at 25 °C for 8 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 = 10:1, v / v). The resulting product sample was noted as 19-2, 39.0 mg in total, with a yield of 84%, an ee value of 96%, and a 84:11:5:0 dr.

[0181] The detection data of product sample 19-2 are as follows:

[0182] colorless oily liquid; 1 H NMR (400 MHz, CDC13) δ 7.30-7.26 (m, 3H), 7.25-7.19 (m, 2H), 7.00-6.98 (m, 2H), 6.92-6.88 (m, 2H), 6.80-6.70 (m, 4H), 5.15 (d, J = 5.0 Hz, 1H), 4.51 (dd, J = 7.4, 5.1 Hz, 1H), 3.89 (q, J = 6.9 Hz, 1H), 3.81 (s, 3H), 3.72 (s, 3H), 3.45 (d, J = 7.4 Hz, 1H), 1.38 (d, J = 6.9 Hz, 3H); 13 C NMR (101 MHz, CDC13) δ 210.1, 159.7, 154.5, 151.7, 139.4, 129.5, 129.2, 128.2, 128.1, 127.5, 117.3, 114.7, 114.3, 82.9, 77.9, 55.8, 55.4, 51.1, 17.4. HRMS (ESI-Quadrupole-Orbitrap) m / z: [M + Na] + Calcd for C 25 H 26 O5Na 429.1472; Found 429.1471. [a] D 27 +58.1 (c 1.1, CHCl3); HPLC analysis: 96% ee (Chiralcel IC, 5:95 i PrOH / hexanes, 1 mL / min, 254 nm), R t (major) = 15.1 min, Rt (minor) = 10.9 min. IR (KBr thin film, cm -1 ): v 2934, 2836, 1713, 1611, 1505, 1453, 1223, 1174, 1031, 824, 700.

[0183] Example 20

[0184]

[0185] A mixture of formic acid and triethylamine (93 μL, n:n=5:2, 10.0 equiv) was dissolved in acetonitrile (1 mL), and aryloxy-substituted unsymmetrical diketone 1-1 (34.6 mg, 0.1 mmol) and Ru catalyst C4 (1.1 mg, 1.5 mol%) were added to the above solution, which was stirred at 25 °C for 3 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 a crude product. The obtained crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, v / v). The obtained product sample was designated as 1-2, 27.8 mg in total, with a yield of 80%, an ee value of 90%, 8:1 dr, and 8:1 rr.

[0186] Example 21

[0187]

[0188] 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 (34.6 mg, 0.1 mmol) and Ru catalyst C1 (1.0 mg, 1.5 mol%) were added to the above solution, which was stirred at 25 °C for 3 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 a crude product. The obtained crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, v / v). The obtained product sample was designated as 1-2, 28.8 mg in total, with a yield of 83%, an ee value of 88%, 11:1 dr, and 8:1 rr.

[0189] Example 22

[0190]

[0191] A mixture of formic acid and tetramethylethylenediamine (98 μL, n:n=5:2, 10.0 equiv) was dissolved in acetonitrile (1 mL), and aryl-oxygen substituted unsymmetrical diketone 1-1 (34.6 mg, 0.1 mmol) and Ru catalyst C8 (1.0 mg, 1.5 mol%) were added to the above solution. The reaction was stirred at 25 °C for 3 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 resulting organic phase was dried over anhydrous sodium sulfate and then rotary evaporated to give the crude product. The resulting crude product was isolated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, v / v). The resulting product sample was noted as 1-2, 27.8 mg in total, 80% yield, 83% ee, 10:1 dr, 8:1 rr.

[0192] Example 23

[0193]

[0194] A mixture of formic acid and tetramethylethylenediamine (158 μL, n:n=5:4, 10.0 equiv) was dissolved in acetonitrile (1 mL), and aryl-oxygen substituted unsymmetrical diketone 13-1 (37.4 mg, 0.1 mmol) and Ru catalyst C1 (1.0 mg, 1.5 mol%) were added to the above solution. The reaction was stirred at 25 °C for 8 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 resulting organic phase was dried over anhydrous sodium sulfate and then rotary evaporated to give the crude product. The resulting crude product was isolated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, v / v). The resulting product sample was noted as 13-2, 31.2 mg in total, 83% yield, 84% ee, 57:32:11:0 dr.

[0195] Example 24

[0196]

[0197] A mixture of formic acid and tetramethylethylenediamine (158 μL, n:n=5:4, 10.0 equiv) was dissolved in acetonitrile (1 mL), and aryl-oxygen substituted unsymmetrical diketone 13-1 (37.4 mg, 0.1 mmol) and Ru catalyst C8 (1.0 mg, 1.5 mol%) were added to the above solution. The reaction was stirred at 25 °C for 8 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 resulting organic phase was dried over anhydrous sodium sulfate and then rotary evaporated to give the crude product. The resulting crude product was isolated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, v / v). The resulting product sample was noted as 13-2, 22.9 mg in total, 61% yield, 51% ee, 67:23:10:0 dr.

[0198] The above is only a few embodiments of the present application, and does not limit the present application in any form. Although the preferred embodiments are disclosed above, the present application is not limited thereto. Any person skilled in the art can make some changes or modifications to the disclosed technical content without departing from the scope 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 α-hydroxy ketone, characterized in that The application relates to a method for preparing a chiral aryloxy-substituted chiral alpha-hydroxy ketone. The method comprises the following steps: The method comprises the following steps: Preferably, the non-hydrocarbon group is selected from oxygen, halogen, a group having the structure shown in formula (1), a group having the structure shown in formula (2) or a group having the structure shown in formula (3): 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 hydrogen, 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 hydrogen, 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 halogen comprises F, Cl, Br and I. 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; The chiral catalyst is selected from a chiral metal complex-based catalyst.

5. The method of claim 1, wherein, Preferably, the chiral catalyst is selected from at least one of the following catalysts C1-C11: Preferably, the molar ratio of the aryloxy-substituted asymmetric diketone to the chiral catalyst is 1:(0.005-0.035). Preferably, the molar ratio of the aryloxy-substituted asymmetric diketone to the chiral catalyst is 1:(0.01-0.03). The transfer hydrogenation reagent is selected from at least one of the following: ammonium formate, sodium formate, isopropyl alcohol, formic acid / amine azeotrope.

6. The method of claim 1, wherein, Preferably, the formic acid / amine azeotrope is selected from at least one of the following: 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. Preferably, the molar ratio of the transfer hydrogenation reagent to the aryloxy-substituted asymmetric diketone is (5-20):1; preferably (8-16):

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

7. The method of claim 1, wherein, The reaction temperature is 5-40 DEG C, and the reaction time is 1-10 h.

8. The method of claim 1, wherein, Preferably, the reaction temperature is 10-35 DEG C, and the reaction time is 3-8 h. The method further comprises the step of separating and purifying the chiral aryloxy-substituted chiral alpha-hydroxy ketone.

9. The method of claim 1, wherein, The method comprises the following steps:

10. The method according to any one of claims 1-9, characterized in that, a) placing a mixture containing the aryloxy-substituted asymmetric diketone, the transfer hydrogenation reagent and the chiral catalyst in a reaction container, stirring at 5-40 DEG C for 1-10 h to perform the transfer hydrogenation reaction, and obtaining a reaction product; b) extracting the reaction product, concentrating the obtained organic phase, and obtaining a crude chiral aryloxy-substituted chiral alpha-hydroxy ketone product; c) purifying the crude product through silica gel column chromatography, and obtaining a purified chiral aryloxy-substituted chiral alpha-hydroxy ketone. ​

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