Preparation method of chiral cis-cyclobutenediol

Abstract

The invention discloses a preparation method of chiral cis-cyclobutenediol, which comprises the following step: in the presence of a chiral catalyst and a transfer hydrogenation reagent, carrying out selective transfer hydrogenation reaction on cyclobutenedione to generate the chiral cis-cyclobutenediol. 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 cyclobutenedione, the chiral cis-cyclobutenediol core skeleton with four continuous three-dimensional centers is prepared with high selectivity, the synthesis route is direct, and the atom economy is high.

Description

Technical Field

[0001] The present application relates to a method for preparing chiral cis-cyclobutenediol, and belongs to the field of chemical synthesis. Background Art

[0002] The past decade has seen rapid progress in the catalytic asymmetric synthesis of cyclobutanes and their derivatives, including [2+2] cycloadditions and skeletal rearrangements such as ring expansions or contractions. Despite these remarkable achievements, accessing chiral four-membered ring scaffolds in a concise, highly selective, and versatile manner remains challenging. In this context, the enantioselective functionalization of pre-existing four-membered substrates has attracted considerable attention from chemists.

[0003] Cyclobutenediones, readily available and highly functionalized four-membered ring compounds, have been used in organic synthesis for over half a century, but their successful application in catalytic asymmetric transformations has never been successful. The challenge stems primarily from regioselective control, as both carbonyl groups are reactive, potentially exposing the double bond to attack from both sides. A second reason is that cyclobutenediones readily undergo ring-opening reactions, yielding linear or ring-expanded compounds. Summary of the Invention

[0004] In view of the above, the purpose of this application is to provide a method for preparing chiral cis-cyclobutenediol. This method uses a chiral metal complex as a catalyst and cyclobutenedione as a starting material to achieve selective transfer hydrogenation in the presence of a transfer hydrogenation reagent, thereby producing the core skeleton of the chiral cis-cyclobutenediol.

[0005] The present application provides a method for preparing chiral cis-cyclobutenediol, comprising:

[0006] In the presence of an organic solvent, a chiral catalyst and a transfer hydrogenation reagent, cyclobutenedione is subjected to a selective transfer hydrogenation reaction to generate chiral cis-cyclobutenediol.

[0007] Wherein, the cyclobutenedione has a structure shown in Formula II:

[0008]

[0009] The chiral cis-cyclobutenediol has a structure shown in Formula I:

[0010]

[0011] Among them, R 1 、R 2 、R 3 、R 4 、R 5 、R 6Each is independently selected from one of hydrogen, hydrocarbon, substituted hydrocarbon, heteroaryl, substituted heteroaryl or non-hydrocarbon groups;

[0012] Optionally, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 Each independently selected from hydrogen, C1-C 20 Hydrocarbon, C1-C 20 Substituted hydrocarbon, C5-C 20 Heteroaryl, C5-C 20 substituted heteroaryl or non-hydrocarbon groups;

[0013] Preferably, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 Each independently selected from hydrogen, C1-C 10 Alkyl, C1-C 10 substituted alkyl or non-hydrocarbon groups;

[0014] Optionally, the substituents in the substituted hydrocarbon group or substituted heteroaryl group are each independently selected from C1-C 10 Hydrocarbon or non-hydrocarbon groups;

[0015] Preferably, 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):

[0016]

[0017]

[0018] M 31 -O- Formula (3)

[0019] Among them, M 11 、M 21 and M 31 independently selected from hydrogen or C1-C 10 alkyl.

[0020] Optionally, R 1 、R 2 、R 3 、R 4 、R 5 Each independently selected from hydrogen, C1-C 10 Alkyl, C1-C 10 Alkoxy or halogen;

[0021] R 6 Selected from C1-C 10 Alkyl, C1-C 10 Substituted alkyl, C5-C 10 Aryl or C5-C 10 Substituted aryl, wherein the substituents in the substituted alkyl and substituted aryl are each independently selected from C1-C 10 Alkyl, halogen, C1-C 10 At least one of an alkoxy group or a hydroxy group.

[0022] Optionally, the chiral catalyst is selected from catalysts based on chiral metal complexes;

[0023] Preferably, the chiral catalyst is selected from at least one of the following catalysts C1-C11:

[0024]

[0025] Optionally, the molar ratio of the cyclobutenedione to the chiral catalyst is 1:(0.01-0.03).

[0026] Preferably, the molar ratio of the cyclobutenedione to the catalyst is 1:(0.015-0.025).

[0027] Optionally, the transfer hydrogenation reagent is selected from at least one of ammonium formate, sodium formate, isopropanol, and formic acid / amine azeotrope.

[0028] Preferably, 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, formic acid / triethylamine, and formic acid / 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0029] Optionally, the molar ratio of the transfer hydrogenation reagent to the cyclobutenedione is (1-8):1; preferably (2-4):1.

[0030] Optionally, the organic solvent is selected from at least one of acetonitrile, ethyl acetate, dichloromethane, and isopropanol.

[0031] Optionally, the reaction temperature is 10 to 50° C., and the reaction time is 3 to 11 hours;

[0032] Preferably, the reaction temperature is 20-40° C., and the reaction time is 5-9 h.

[0033] Optionally, the method further comprises the step of separating and purifying the chiral cis-cyclobutenediol.

[0034] Optionally, the method comprises the following steps:

[0035] a) placing a mixture comprising the cyclobutenedione, the transfer hydrogenation reagent, and the chiral catalyst in a reaction vessel, stirring at 10-50° C. for 3-11 hours to perform the transfer hydrogenation reaction to obtain a reaction product;

[0036] b) extracting the reaction product and concentrating the obtained organic phase to obtain a crude product;

[0037] c) purifying the crude product by silica gel column chromatography to obtain purified chiral cis-cyclobutenediol.

[0038] The beneficial effects of this application include:

[0039] 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.

[0040] 2) The method provided in this application prepares a chiral cis-cyclobutenediol core skeleton with high selectivity through asymmetric transfer hydrogenation of cyclobutenedione. The synthetic route is direct and atom economy is high. DETAILED DESCRIPTION

[0041] 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.

[0042] In this application, the expression "C1-C 10 ”, “C1-C 20 ” etc. refer to the number of carbon atoms contained in the group.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] In this application, the term "heteroaryl" refers to a group formed by losing any hydrogen atom on the aromatic ring of an aromatic compound (hereinafter referred to as a heteroaromatic compound) containing an O, N or S heteroatom in the aromatic ring, such as a furanyl group formed by losing any hydrogen atom on the furan ring.

[0047] In the present application, the term "halogen" refers to at least one of fluorine, chlorine, bromine, and iodine.

[0048] In this application, the term "non-hydrocarbon group" refers to a group formed by losing any hydrogen atom from a compound containing elements other than H and C (such as halogen, S, O, P, N, etc.); some non-limiting examples include alkoxy, carboxyl, hydroxyl, ester, halogen, sulfonic acid, amino, nitro, etc.

[0049] In this application, the definition 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 heteroaryl group itself, not the number of carbon atoms after substitution. For example, “C1-C 10 The term "substituted alkyl" refers to an alkyl group having 1 to 10 carbon atoms, wherein at least one hydrogen atom on the alkyl group is replaced by a substituent, such as a group having 11 carbon atoms formed by replacing one hydrogen atom on the adamantyl group by C≡N.

[0050] 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.

[0051] 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.

[0052] The present application provides a method for preparing chiral cis-cyclobutenediol, comprising:

[0053] In the presence of an organic solvent, a chiral catalyst and a transfer hydrogenation reagent, cyclobutenedione is subjected to a selective transfer hydrogenation reaction to generate chiral cis-cyclobutenediol.

[0054] Wherein, the cyclobutenedione has a structure shown in Formula II:

[0055]

[0056] The chiral cis-cyclobutenediol has a structure shown in Formula I, i.e., (1R, 2S)-cyclobutenediol:

[0057]

[0058] Among them, R 1 、R2 、R 3 、R 4 、R 5 、R 6 Each is independently selected from one of hydrogen, hydrocarbon, substituted hydrocarbon, heteroaryl, substituted heteroaryl or non-hydrocarbon groups;

[0059] In some embodiments, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 Each independently selected from hydrogen, C1-C 20 Hydrocarbon, C1-C 20 Substituted hydrocarbon, C5-C 20 Heteroaryl, C5-C 20 substituted heteroaryl or non-hydrocarbon groups;

[0060] In some embodiments, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 Each independently selected from hydrogen, C1-C 10 Hydrocarbon, C1-C 10 substituted hydrocarbon or non-hydrocarbon groups;

[0061] In some embodiments, the substituents in the substituted hydrocarbon group or substituted heteroaryl group are each independently selected from C1-C 10 Hydrocarbon or non-hydrocarbon groups;

[0062] 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):

[0063]

[0064]

[0065] M 31 -O- Formula (3)

[0066] Among them, M 11 、M 21 and M 31 independently selected from hydrogen or C1-C 10 alkyl.

[0067] In some embodiments, the non-hydrocarbon group includes oxygen, halogen, hydroxyl, C1-C 10 Carboxyl, C1-C 10Ester group, C1-C 10 Alkoxy, C1-C10 acyloxy.

[0068] In some embodiments, the halogen includes F, Cl, Br, and I.

[0069] In some embodiments, R 1 、R 2 、R 3 、R 4 、R 5 Each independently selected from hydrogen, C1-C 10 Alkyl, C1-C 10 Alkoxy or halogen;

[0070] R 6 Selected from C1-C 10 Alkyl, C1-C 10 Substituted alkyl, C5-C 10 Aryl or C5-C 10 Substituted aryl, wherein the substituents in the substituted alkyl and substituted aryl are each independently selected from C1-C 10 Alkyl, halogen, C1-C 10 At least one of an alkoxy group or a hydroxy group.

[0071] In some embodiments, R 1 、R 2 、R 3 、R 4 、R 5 Each is independently selected from hydrogen, C1-C5 alkyl or C1-C5 alkoxy;

[0072] R 6 Selected from C1-C6 alkyl, C1-C6 substituted alkyl, C5-C 10 Aryl or C5-C 10 Substituted aryl, wherein the substituents in the substituted alkyl and substituted aryl are each independently selected from at least one of C1-C6 alkyl, halogen, C1-C6 alkoxy or hydroxyl.

[0073] In some embodiments, R 1 、R 2 、R 3 、R 4 、R 5 are each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, F, Cl, Br or I;

[0074] R 6is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, cyclohexyl, phenyl, benzyl, phenethyl, and optionally, at least one hydrogen in the group is substituted by halogen, methoxy, methyl or hydroxy.

[0075] In some embodiments, the chiral catalyst is selected from catalysts based on chiral metal complexes.

[0076] In some embodiments, the chiral catalyst is selected from at least one catalyst based on a chiral ruthenium (Ru) complex.

[0077] In some embodiments, the chiral catalyst is selected from at least one of the following catalysts C1-C11:

[0078]

[0079] In some preferred embodiments, the chiral catalyst is catalyst C8.

[0080] In some embodiments, the molar ratio of the cyclobutenedione to the chiral catalyst is 1:(0.01-0.03).

[0081] Optionally, the molar ratio of the cyclobutenedione to the catalyst is independently selected from any value among 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 value therebetween.

[0082] In some preferred embodiments, the molar ratio of the cyclobutenedione to the catalyst is 1:(0.015-0.025).

[0083] In some embodiments, the transfer hydrogenation reagent is selected from at least one of ammonium formate, sodium formate, isopropanol, and formic acid / amine azeotrope;

[0084] 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, formic acid / triethylamine, and formic acid / 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0085] In some preferred embodiments, the transfer hydrogenation reagent is formic acid / 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0086] In some embodiments, in the formic acid / amine azeotrope, the volume ratio of formic acid to amine azeotrope is 5:(2-6).

[0087] In some embodiments, in the formic acid / amine azeotrope, the volume ratio of formic acid to amine azeotrope is independently selected from any value among 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, or any range therebetween.

[0088] In some embodiments, the molar ratio of the transfer hydrogenation reagent to the cyclobutenedione is (1-8):1.

[0089] Optionally, the molar ratio of the transfer hydrogenation reagent to the cyclobutenedione is selected from any value of 1.0:1, 1.3:1, 1.7:1, 2.0:1, 2.3:1, 2.7:1, 3.0:1, 3.3:1, 3.7:1, 4.0:1, 4.3:1, 4.7:1, 5.0:1, 5.5:1, 6.0:1, 6.5:1, 7.0:1, 7.5:1, 8.0:1 or any range value therebetween.

[0090] In some preferred embodiments, the molar ratio of the transfer hydrogenation reagent to the cyclobutenedione is (2-4):1.

[0091] In some embodiments, the organic solvent is selected from at least one of acetonitrile, ethyl acetate, dichloromethane, and isopropanol.

[0092] In some embodiments, the ratio of the cyclobutenedione to the organic solvent is 0.05-0.2 mol / L.

[0093] In some embodiments, the reaction temperature is 10 to 50° C., and the reaction time is 3 to 11 hours;

[0094] Optionally, the reaction temperature of the reaction is independently selected from any value among 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C or any range therebetween.

[0095] Optionally, the reaction time of the reaction is independently selected from any value among 3.0h, 3.5h, 4.0h, 4.5h, 5.0h, 5.5h, 6.0h, 6.5h, 7.0h, 7.5h, 8.0h, 8.5h, 9.0h, 9.5h, 10.0h, 10.5h, 11.0h or any range value therebetween.

[0096] In some preferred embodiments, the reaction temperature is 20-40°C and the reaction time is 5-9 hours. The inventors have found that this reaction temperature and reaction time are conducive to improving the yield of the product. If the reaction temperature is too high or too low, or the reaction time is too short, more other products will be generated.

[0097] In some embodiments, the method comprises the following steps:

[0098] A mixture comprising cyclobutenedione represented by formula II, a transfer hydrogenation agent and a chiral catalyst is placed in a reaction vessel and stirred at 10 to 50° C. for 3 to 11 hours to perform a transfer hydrogenation reaction to obtain a reaction product represented by formula I.

[0099] In some embodiments, the method further comprises the step of separating and purifying the chiral cis-cyclobutenediol.

[0100] In some embodiments, the method comprises the following steps:

[0101] a) placing a mixture comprising the cyclobutenedione, the transfer hydrogenation reagent, the chiral catalyst, and the additive in a reaction vessel, stirring at 10 to 50° C. for 3 to 11 hours to perform the transfer hydrogenation reaction to obtain a reaction product;

[0102] b) extracting the reaction product and concentrating the obtained organic phase to obtain a crude product;

[0103] c) purifying the crude product by silica gel column chromatography to obtain purified chiral cis-cyclobutenediol.

[0104] In some embodiments, the extraction is performed using ethyl acetate.

[0105] In some embodiments, the concentrating comprises drying over anhydrous sodium sulfate and rotary evaporation.

[0106] In some embodiments, the concentrating is performed under reduced pressure.

[0107] In a specific embodiment, the transfer hydrogenation reaction is carried out at 20-40° C. with stirring for 5-9 hours.

[0108] The present application is described in detail below with reference to embodiments, but the present application is not limited to these embodiments.

[0109] Unless otherwise specified, the raw materials and reagents in the examples of this application were purchased through commercial channels.

[0110] The instruments used in the examples of this application are as follows:

[0111] 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.

[0112] The yield of chiral cis-cyclobutenediol is based on the amount of cyclobutenedione and is calculated by the following formula:

[0113] Yield % = (actual mass of target product obtained ÷ theoretical mass of target product) × 100%

[0114] The meanings of the abbreviations that may be involved in the examples of this application are as follows: Me is methyl; Et is ethyl; n Bu is n-butyl; HCOOH is formic acid; DBU is 1,8-diazabicyclo[5.4.0]undec-7-ene; NMR is nuclear magnetic resonance; chiral HPLC is high performance liquid chromatography equipped with a chiral column; ee value is the enantiomeric excess ratio; dr represents the diastereomeric ratio; TLC is thin layer chromatography.

[0115] 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 cyclobutenedione; the amount of transfer hydrogenation reagent used is expressed as the molar equivalent of transfer hydrogenation reagent relative to cyclobutenedione.

[0116] Example 1

[0117]

[0118] A mixture of formic acid (11.3 μL, 3 equiv) and 1,8-diazabicyclo[5.4.0]undec-7-ene (CAS No. 6674-22-2, 35.8 μL, 2.4 equiv) was dissolved in a mixture of ethyl acetate / acetonitrile (4:1, 1.4 mL). Cyclobutenedione 1-1 (27.4 mg, 0.1 mmol) and Ru catalyst C8 (1.3 mg, 2 mol%) were added to the solution and stirred at 30°C for 7 hours. After completion of the reaction was confirmed by TLC, the reaction system was extracted with ethyl acetate (3 × 5 mL). The resulting organic phase was dried over anhydrous sodium sulfate and rotary evaporated to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1, v / v). The resulting product, designated 1-2, contained 16.6 mg of product with a yield of 61%, an ee of 91%, and a dr of 20:1.

[0119] The test data of product sample 1-2 are as follows:

[0120] Colorless oily liquid; 1 H NMR (600MHz, CDCl3) δ7.57-7.54(m,2H),7.40-7.34(m,6H),7.31-7.28(m,1H),7.26-7.23(m,1H),7.00(s,1H),5.01(d d,J=6.7,3.8Hz,1H),4.97(dd,J=6.8,3.8Hz,1H),2.60(t,J=7.8Hz,1H),2.57(t,J=7.8Hz,1H),2.08(d,J=1.3Hz,3H). 13 C NMR (151MHz, CDCl3) δ148.0,144.2,137.1,133.7,132.0,130.9,129.5,128.4,128 .3,128.2,127.3,70.6,70.4,16.8.HRMS(ESI-Quadrupole-Orbitrap)m / z:[M+Na] + Calcd for C 19 H 18 NaO2 301.1199; Found:301.1200.[α] D 29 :+23.6 (c 0.1, CHCl3); HPLC analysis: 91%ee (Chiralcel IA, 10:90 i PrOH / hexanes, 1 mL / min, 254 nm), R t (major)=7.6min,R t(minor)=6.1min.IR(KBr thin film,cm -1 ):ν3852,3648,2989,2359,2342,1684,1558,1457,1275,1260,669.

[0121] Example 2

[0122]

[0123] A mixture of formic acid (11.3 μL, 3 equiv) and 1,8-diazabicyclo[5.4.0]undec-7-ene (35.8 μL, 2.4 equiv) was dissolved in a mixture of ethyl acetate / acetonitrile (4:1, 1.4 mL). Cyclobutenedione 2-1 (35.2 mg, 0.1 mmol) and Ru catalyst C8 (1.3 mg, 2 mol%) were added to the solution and stirred at 30°C for 7 hours. After completion of the reaction as confirmed by TLC, the reaction system was extracted with ethyl acetate (3 × 5 mL). The resulting organic phase was dried over anhydrous sodium sulfate and rotary evaporated to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1, v / v). The resulting product, designated 2-2, contained 19.6 mg of the product with a yield of 55%, an ee of 90%, and a dr of 20:1.

[0124] The test data of product sample 2-2 is as follows:

[0125] Colorless oily liquid; 1 H NMR (400MHz, CDCl3) δ7.55(d,J=7.0Hz,2H),7.48(d,J=8.4Hz,2H),7.40-7.31(m,3H),7.24(d,J=8. 5Hz,2H),6.92(s,1H),5.02-4.97(m,2H),2.54(d,J=6.7Hz,1H),2.48(d,J=6.5Hz,1H),2.06(s,3H). 13 C NMR (101MHz, CDCl3) δ147.6,144.6,135.9,133.4,131.5,131.4,130.9,130.7,128.5, 128.4,128.1,121.1,70.5,70.3,16.7.HRMS(ESI-Quadrupole-Orbitrap)m / z:[M+Na] + Calcd for C 19 H 17 BrNaO2 379.0304; Found:379.0302.[α] D20 :+44.3 (c 0.1, CHCl3); HPLC analysis: 90%ee (Chiralcel As-H, 2:98 i PrOH / hexanes, 1 mL / min, 254 nm), R t (major)=37.3min,R t (minor)=30.4min.IR(KBrthin film,cm -1 ):ν3852,3734,2359,1682,1558,1506,1281,1274,1259,668.

[0126] Example 3

[0127]

[0128] A mixture of formic acid (11.3 μL, 3 equiv) and 1,8-diazabicyclo[5.4.0]undec-7-ene (35.8 μL, 2.4 equiv) was dissolved in a mixture of ethyl acetate / acetonitrile (4:1, 1.4 mL). Cyclobutenedione 3-1 (36.4 mg, 0.1 mmol) and Ru catalyst C8 (1.3 mg, 2 mol%) were added to the solution and stirred at 30°C for 7 hours. After completion of the reaction as confirmed by TLC, the reaction system was extracted with ethyl acetate (3 × 5 mL). The resulting organic phase was dried over anhydrous sodium sulfate and rotary evaporated to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1, v / v). The resulting product, designated 3-2, contained 25.7 mg of product with a yield of 70%, an ee of 84%, and a dr of 20:1.

[0129] The test data of product sample 3-2 are as follows:

[0130] Colorless oily liquid; 1 H NMR (400MHz, CDCl3) δ7.56 (d, J = 7.3Hz, 2H), 7.38 (t, J = 7.4Hz, 2H), 7.34-7.29 (m, 1H), 6.95 (s, 1H) ,6.62(s,2H),5.01(s,2H),3.88(s,9H),2.56(d,J=6.4Hz,1H),2.49(d,J=5.8Hz,1H),2.11(s,3H). 13C NMR (151MHz, CDCl3) δ153.0,148.0,144.1,137.5,133.7,132.7,132.2,130.4,128.5,128.4 ,128.2,106.7,70.6,70.4,61.1,56.2,17.0.HRMS(ESI-Quadrupole-Orbitrap)m / z:[M+Na] + Calcd for C 22 H 24 NaO5391.1516; Found:391.1520.[α] D 20 :+47.3 (c 0.3, CHCl3); HPLC analysis: 84%ee (Chiralcel OD-H, 5:95 i PrOH / hexanes, 1 mL / min, 220 nm), R t (major)=38.5min,R t (minor)=34.1min.IR(KBr thin film,cm -1 ):ν3734,3648,3005,2360,2342,1652,1558,1456,1275,1260.

[0131] Example 4

[0132]

[0133] A mixture of formic acid (11.3 μL, 3 equiv) and 1,8-diazabicyclo[5.4.0]undec-7-ene (35.8 μL, 2.4 equiv) was dissolved in a mixture of ethyl acetate / acetonitrile (4:1, 1.4 mL). Cyclobutenedione 4-1 (28.8 mg, 0.1 mmol) and Ru catalyst C8 (1.3 mg, 2 mol%) were added to the solution and stirred at 30°C for 7 hours. After completion of the reaction as confirmed by TLC, the reaction system was extracted with ethyl acetate (3 × 5 mL). The resulting organic phase was dried over anhydrous sodium sulfate and rotary evaporated to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1, v / v). The resulting product, designated 4-2, contained 17.5 mg of the product with a yield of 60%, an ee of 85%, and a dr of 20:1.

[0134] The test data of product sample 4-2 are as follows:

[0135] Colorless oily liquid; 11H NMR (400 MHz, CDCl3) δ 7.58 - 7.52 (m, 2H), 7.36 (t, J = 7.3 Hz, 2H), 7.32 - 7.27 (m, 3H), 7.17 (d, J = 8.0 Hz, 2H), 6.97 (s, 1H), 5.00 (d, J = 3.5 Hz, 1H), 4.97 (d, J = 3.4 Hz, 1H), 2.69 (s, 2H), 2.36 (s, 3H), 2.08 (d, J = 0.9 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 148.1, 143.8, 137.2, 134.3, 133.8, 132.1, 130.1, 129.5, 129.1, 128.4, 128.3, 128.2, 70.6, 70.4, 21.4, 16.9. HRMS (ESI-Quadrupole-Orbitrap) m / z: [M+Na] + Calcd for C 20 H 20 NaO2315.1356; Found: 315.1355. [α] D 20 : +43.0 (c 1.1, CHCl3); HPLC analysis: 85% ee (Chiralcel OD-H, 3:97 i PrOH / hexanes, 1 mL / min, 254 nm), R t (major) = 17.6 min, R t (minor) = 15.7 min. IR (KBr thin film, cm -1 ): ν 3852, 3734, 2359, 2342, 1684, 1558, 1507, 1275, 1260, 668.

[0136] Example 5

[0137]

[0138] A mixture of formic acid (11.3 μL, 3 equiv) and 1,8-diazabicyclo[5.4.0]undec-7-ene (35.8 μL, 2.4 equiv) was dissolved in a mixture of ethyl acetate / acetonitrile (4:1, 1.4 mL). Cyclobutenedione 5-1 (35.2 mg, 0.1 mmol) and Ru catalyst C8 (1.3 mg, 2 mol%) were added to the solution and stirred at 30°C for 7 hours. After completion of the reaction was confirmed by TLC, the reaction system was extracted with ethyl acetate (3 × 5 mL). The resulting organic phase was dried over anhydrous sodium sulfate and rotary evaporated to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1, v / v). The resulting product, designated 5-2, contained 24.9 mg of product with a yield of 70%, an ee of 90%, and a dr of 20:1.

[0139] The test data of product sample 5-2 are as follows:

[0140] Colorless oily liquid; 1 H NMR(400MHz, CDCl3) δ7.50(d,J=8.6Hz,2H),7.37-7.27(m,4H),6.93-6.85(m,3H),4.98(d,J=3.6Hz ,1H),4.94(d,J=3.6Hz,1H),4.05(q,J=7.0Hz,2H),2.58(s,2H),2.08(s,3H),1.43(t,J=7.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ159.3,145.6,144.3,135.7,132.8,131.7,130.7,130.1,129.7,128.5 ,125.9,114.4,70.6,70.3,63.6,16.9,14.9.HRMS(ESI-Quadrupole-Orbitrap)m / z:[M+Na] + Calcd for C 21 H 21 ClNaO3379.1071; Found:379.1080.[α] D 29 :+40.1 (c 0.72, CHCl3); HPLC analysis: 90%ee (Chiralcel OD-H, 3:97 i PrOH / hexanes, 1 mL / min, 254 nm), R t (major)=19.5min,R t(minor)=25.0min.IR(KBr thin film,cm -1 ):ν3852,3735,3648,2359,2342,1733,1683,1507,1457,1260.

[0141] Example 6

[0142]

[0143] A mixture of formic acid (11.3 μL, 3 equiv) and 1,8-diazabicyclo[5.4.0]undec-7-ene (35.8 μL, 2.4 equiv) was dissolved in a mixture of ethyl acetate / acetonitrile (4:1, 1.4 mL). Cyclobutenedione 6-1 (34.6 mg, 0.1 mmol) and Ru catalyst C8 (1.3 mg, 2 mol%) were added to the solution and stirred at 30°C for 7 hours. After TLC confirmation of the reaction completion, the reaction system was extracted with ethyl acetate (3 × 5 mL). The resulting organic phase was dried over anhydrous sodium sulfate and rotary evaporated to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1, v / v). The resulting product, designated 6-2, contained 23.8 mg of product with a yield of 68%, an ee of 85%, and a dr of 20:1.

[0144] The test data of product sample 6-2 are as follows:

[0145] Colorless oily liquid; 1 H NMR (400MHz, CD3OD) δ7.43(d,J=8.1Hz,2H),7.23(d,J=8.5Hz,2H),7.15(d,J=8.1Hz,2H),6.86(s,1H),6.79-6.73(m,2H), 4.84(dd,J=15.9,3.7Hz,2H),2.59(t,J=7.6Hz,2H),2.02(s,3H),1.62-1.53(m,2H),1.39-1.29(m,2H),0.95-0.88(m,3H). 13 C NMR (101MHz, CD3OD) δ156.5,147.3,142.9,142.7,131.7,131.2,130.6,128.8,128.3,127.9,127. 8,114.8,70.8,70.6,35.2,33.6,22.0,15.9,13.0.HRMS(ESI-Quadrupole-Orbitrap)m / z:[M+Na] + Calcd for C 23 H26 NaO3 373.1774; Found:373.1776.[α] D 29 :+50.0 (c 1.0, CHCl3); HPLC analysis: 85%ee (Chiralcel IC, 5:95 i PrOH / hexanes, 1 mL / min, 254 nm), R t (major)=21.4min,R t (minor)=25.7min.IR(KBr thin film,cm -1 ):ν3852,3734,2928,2358,2343,1604,1507,1275,1260,834.

[0146] Example 7

[0147]

[0148] A mixture of formic acid (11.3 μL, 3 equiv) and 1,8-diazabicyclo[5.4.0]undec-7-ene (35.8 μL, 2.4 equiv) was dissolved in a mixture of ethyl acetate / acetonitrile (4:1, 1.4 mL). Cyclobutenedione 7-1 (32.2 mg, 0.1 mmol) and Ru catalyst C8 (1.3 mg, 2 mol%) were added to the solution and stirred at 30°C for 7 hours. After completion of the reaction as confirmed by TLC, the reaction system was extracted with ethyl acetate (3 × 5 mL). The resulting organic phase was dried over anhydrous sodium sulfate and rotary evaporated to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1, v / v). The resulting product, designated 7-2, contained 14.7 mg of product with a yield of 45%, an ee of 69%, and a dr of 20:1.

[0149] The test data of product sample 7-2 is as follows:

[0150] Colorless oily liquid; 1 H NMR (400MHz, CDCl3) δ7.52-7.45(m,2H),7.33-7.29(m,2H),7.27(d,J=8.1Hz,2H),7.17(d,J=8.0Hz,2H),6 .95(s,1H),4.99(d,J=3.7Hz,1H),4.93(d,J=3.7Hz,1H),2.59(s,1H),2.35(s,3H),2.05(d,J=0.8Hz,3H). 13C NMR (101MHz, CDCl3) δ148.7,142.3,137.4,134.1,134.1,132.5,132.2,129.7,129.5,12 9.4,129.1,128.6,70.6,70.4,21.4,16.9.HRMS(ESI-Quadrupole-Orbitrap)m / z:[M+Na] + Calcd for C 20 H 19 ClNaO2349.0966; Found:349.0964.[α] D 20 :-69.1 (c 0.5, CHCl3); HPLC analysis: 69%ee (Chiralcel OD-H, 2:98 i PrOH / hexanes, 1 mL / min, 220 nm), R t (major)=28.1min,R t (minor)=25.7min.IR(KBr thin film,cm -1 ):ν3852,3335,2920,2359,2341,1733,1488,1275,1262,1090.

[0151] Example 8

[0152]

[0153] A mixture of formic acid (38 μL, 10 equivalents) and tetramethylethylenediamine (120 μL, 8 equivalents) was dissolved in acetonitrile (0.5 mL). Cyclobutenedione 1-1 (27.4 mg, 0.1 mmol) and Ru catalyst C1 (1.3 mg, 2 mol%) were added to the above solution and stirred at 30°C for 7 hours. After TLC plate analysis confirmed the completion of the reaction, the reaction system was extracted with ethyl acetate (3 × 5 mL). The resulting organic phase was dried over anhydrous sodium sulfate and rotary evaporated to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1, v / v). The resulting product sample was designated 1-2 and contained 6.8 mg of the product with a yield of 25%, an ee value of 65%, and a dr ratio of 3:1.

[0154] Example 9

[0155]

[0156] A mixture of formic acid (38 μL, 10 equivalents) and triethylamine (111 μL, 8 equivalents) was dissolved in acetonitrile (0.5 mL). Cyclobutenedione 1-1 (27.4 mg, 0.1 mmol) and Ru catalyst C8 (1.3 mg, 2 mol%) were added to the above solution and stirred at 30°C for 7 hours. After TLC plate analysis confirmed the completion of the reaction, the reaction system was extracted with ethyl acetate (3 × 5 mL). The resulting organic phase was dried over anhydrous sodium sulfate and rotary evaporated to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1, v / v). The resulting product sample, designated 1-2, contained 17.7 mg of product with a yield of 65%, an ee value of 71%, and an 11:1 dr.

[0157] The above descriptions are merely a few embodiments of the present application and do not constitute any form of limitation to the present application. Although the present application discloses the preferred embodiments as above, they are not intended to limit the present application. Any technical personnel familiar with the present profession, without departing from the scope of the technical solution of the present application, using the technical content disclosed above to make slight changes or modifications are equivalent to equivalent implementation cases and fall within the scope of the technical solution.

Claims

1. A method for preparing chiral cis-cyclobutenediol, characterized in that: include: In the presence of an organic solvent, a chiral catalyst and a transfer hydrogenation reagent, cyclobutenedione is subjected to a selective transfer hydrogenation reaction to generate chiral cis-cyclobutenediol. Wherein, the cyclobutenedione has a structure shown in Formula II: The chiral cis-cyclobutenediol has a structure shown in Formula I: Among them, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 Each is independently selected from one of hydrogen, hydrocarbon group, substituted hydrocarbon group, heteroaryl group, substituted heteroaryl group or non-hydrocarbon group.

2. The method according to claim 1, characterized in that R 1 、R 2 、R 3 、R 4 、R 5 、R 6 Each independently selected from hydrogen, C1-C 20 Hydrocarbon, C1-C 20 Substituted hydrocarbon, C5-C 20 Heteroaryl, C5-C 20 substituted heteroaryl or non-hydrocarbon groups; Preferably, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 Each independently selected from hydrogen, C1-C 10 Hydrocarbon, C1-C 10 Substituted hydrocarbon or non-hydrocarbon groups.

3. The method according to claim 1, characterized in that The substituents in the substituted hydrocarbon group or substituted heteroaryl group are each independently selected from C1-C 10 Hydrocarbon or non-hydrocarbon groups; Preferably, 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): M 31 -O- Formula (3) Among them, M 11 、M 21 and M 31 independently selected from hydrogen or C1-C 10 alkyl.

4. The method according to claim 1, wherein R 1 、R 2 、R 3 、R 4 、R 5 Each independently selected from hydrogen, C1-C 10 Alkyl, C1-C 10 Alkoxy or halogen; R 6 Selected from C1-C 10 Alkyl, C1-C 10 Substituted alkyl, C5-C 10 Aryl or C5-C 10 Substituted aryl, wherein the substituents in the substituted alkyl and substituted aryl are each independently selected from C1-C 10 Alkyl, halogen, C1-C 10 At least one of an alkoxy group or a hydroxy group.

5. The method according to claim 1, wherein The chiral catalyst is selected from catalysts based on chiral metal complexes; Preferably, the chiral catalyst is selected from at least one of the following catalysts C1-C11: Preferably, the molar ratio of the cyclobutenedione to the chiral catalyst is 1:(0.01-0.03); Preferably, the molar ratio of the cyclobutenedione to the catalyst is 1:(0.015-0.025).

6. The method according to claim 1, characterized in that The transfer hydrogenation reagent is selected from at least one of ammonium formate, sodium formate, isopropyl alcohol, and formic acid / amine azeotrope; Preferably, 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, formic acid / triethylamine, and formic acid / 1,8-diazabicyclo[5.4.0]undec-7-ene; Preferably, the molar ratio of the transfer hydrogenation reagent to the cyclobutenedione is (1-8):1; preferably (2-4):

1.

7. The method according to claim 1, characterized in that The organic solvent is selected from at least one of acetonitrile, ethyl acetate, dichloromethane and isopropyl alcohol.

8. The method according to claim 1, characterized in that The reaction temperature of the reaction is 10-50°C and the reaction time is 3-11h; Preferably, the reaction temperature is 20-40° C., and the reaction time is 5-9 h.

9. The method according to claim 1, characterized in that The method also includes the step of separating and purifying the chiral cis-cyclobutenediol.

10. The method according to any one of claims 1 to 9, characterized in that The following steps are involved: a) placing a mixture comprising the cyclobutenedione, the transfer hydrogenation reagent, and the chiral catalyst in a reaction vessel, stirring at 10-50° C. for 3-11 hours to perform the transfer hydrogenation reaction to obtain a reaction product; b) extracting the reaction product and concentrating the obtained organic phase to obtain a crude product; c) purifying the crude product by silica gel column chromatography to obtain purified chiral cis-cyclobutenediol.

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