Preparation method of chiral cis-cyclobutanediol

Abstract

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

Description

Technical Field

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

[0002] Four-membered carbon rings contain highly strained molecular structures and exhibit unique conformational properties, making them important building blocks in organic synthesis and serving as a building block for a variety of bioactive substances, such as natural products and approved drugs. 1-Aryl-2-alkyl-cyclobutanes are a significant subclass, with many patented drug candidates or drug molecule derivatives possessing 1-aryl-2-alkyl-cyclobutane structures.

[0003]

[0004] Currently available methods for preparing chiral cyclobutanes often have drawbacks such as multiple steps, low efficiency, harsh reaction conditions, and a lack of universality. However, there are no reports on the preparation of chiral cyclobutanes with four consecutive stereocenters. Therefore, developing efficient and highly selective methods for preparing chiral cyclobutane skeletons with four consecutive stereocenters is particularly important. The two hydroxyl groups of cyclobutanediol can be easily converted into alkyl groups, thereby enabling the efficient synthesis of chiral cyclobutanes. Summary of the Invention

[0005] In view of the above, the purpose of this application is to provide a method for preparing chiral cis-cyclobutanediol. This method uses a chiral metal complex as a catalyst and cyclobutenedione as a starting material, and selectively transfer hydrogenates with the addition of a Lewis acid to produce a chiral cis-cyclobutanediol core skeleton having four consecutive stereocenters.

[0006] According to the present application, a method for preparing chiral cis-cyclobutanediol is provided, comprising:

[0007] In the presence of a chiral catalyst, a Lewis acid compound and a transfer hydrogenation reagent, cyclobutenedione is subjected to a selective transfer hydrogenation reaction to generate chiral cis-cyclobutanediol.

[0008] Wherein, the cyclobutenedione has a structure shown in Formula II:

[0009]

[0010] The chiral cis-cyclobutanediol has a structure shown in Formula I:

[0011]

[0012] Among them, R 1 、R 2 、R 3 、R4 、R 5 are each independently selected from hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroaryl, substituted heteroaryl, or a non-hydrocarbon group;

[0013] R 6 is selected from alkyl, substituted alkyl, heteroaryl, substituted heteroaryl or non-hydrocarbon groups.

[0014] Optionally, R 1 、R 2 、R 3 、R 4 、R 5 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;

[0015] R 6 Selected from C1-C 20 Alkyl, C1-C 20 Substituted alkyl, C5-C 20 Heteroaryl, C5-C 20 substituted heteroaryl or non-hydrocarbon groups;

[0016] Preferably, R 1 、R 2 、R 3 、R 4 、R 5 Each independently selected from hydrogen, C1-C 10 Hydrocarbon, C1-C 10 substituted hydrocarbon or non-hydrocarbon groups;

[0017] R 6 Selected from C1-C 10 Alkyl, C1-C 10 substituted alkyl or non-hydrocarbon groups;

[0018] Optionally, the substituents in the substituted alkyl, substituted hydrocarbon or substituted heteroaryl are each independently selected from C1-C 10 Hydrocarbon, C5-C 10 heteroaryl or non-hydrocarbon groups;

[0019] 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):

[0020]

[0021] M 31 -O- Formula (3)

[0022] Among them, M 11 、M 21 and M 31 independently selected from hydrogen or C1-C 10 alkyl.

[0023] 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;

[0024] R 6 Selected from C1-C 10 Alkyl or C1-C 10 The substituted alkyl group is a substituted alkyl group, wherein the substituent in the substituted alkyl group is selected from at least one of halogen and phenyl.

[0025] Optionally, the chiral catalyst is selected from catalysts based on chiral metal complexes;

[0026] Preferably, the chiral catalyst is selected from at least one of the following catalysts C1-C11:

[0027]

[0028] Optionally, the Lewis acid compound is selected from at least one of lithium chloride, magnesium chloride, scandium chloride, zinc chloride, titanium tetrachloride, lithium trifluoromethanesulfonate, magnesium trifluoromethanesulfonate, scandium trifluoromethanesulfonate, zinc trifluoromethanesulfonate, and isopropyl titanate.

[0029] Optionally, the molar ratio of the cyclobutenedione, the chiral catalyst and the Lewis acid compound is 1:(0.03-0.05):(0.1-0.3);

[0030] Preferably, the molar ratio of the cyclobutenedione, the catalyst and the Lewis acid compound is 1:(0.035-0.045):(0.15-0.25).

[0031] Optionally, the transfer hydrogenation reagent is selected from at least one of ammonium formate, sodium formate, isopropanol, and formic acid / amine azeotrope;

[0032] 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, and formic acid / triethylamine.

[0033] Optionally, the molar ratio of the transfer hydrogenation reagent to the cyclobutenedione is (5-20):1; preferably (8-15):1.

[0034] Optionally, the reaction temperature is 5 to 40° C., and the reaction time is 2 to 8 hours;

[0035] Preferably, the reaction temperature is 10-35° C., and the reaction time is 3-6 h.

[0036] Optionally, the method further comprises the step of separating and purifying the chiral cis-cyclobutanediol.

[0037] Optionally, the method comprises the following steps:

[0038] a) placing a mixture comprising the cyclobutenedione, the transfer hydrogenation reagent, the chiral catalyst, and the Lewis acid compound in a reaction vessel, stirring at 5 to 40° C. for 2 to 8 hours to perform the transfer hydrogenation reaction to obtain a reaction product;

[0039] b) extracting the reaction product and concentrating the obtained organic phase to obtain a crude product;

[0040] c) purifying the crude product by silica gel column chromatography to obtain purified chiral cis-cyclobutanediol.

[0041] The beneficial effects of this application include:

[0042] 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.

[0043] 2) The method provided in this application uses asymmetric transfer hydrogenation of cyclobutenedione to highly selectively prepare a chiral cis-cyclobutanediol core skeleton with four consecutive stereocenters. The synthetic route is direct and has high atom economy. DETAILED DESCRIPTION

[0044] 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.

[0045] In this application, the expression "C1-C 10 ”, “C1-C 20 ” etc. refer to the number of carbon atoms contained in the group.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] In the present application, the term "halogen" refers to at least one of fluorine, chlorine, bromine, and iodine.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] In this application, "Lewis acid" or "Lewis acid compound", also known as an electrophilic reagent, refers to a substance (including ions, atomic groups or molecules) that can accept electron pairs. This is determined based on the definition of acid in Gilbert Newton Lewis's acid-base electronic theory.

[0056] The present application provides a method for preparing chiral cis-cyclobutanediol, comprising:

[0057] In the presence of a chiral catalyst, a Lewis acid compound and a transfer hydrogenation reagent, cyclobutenedione is subjected to a selective transfer hydrogenation reaction to generate chiral cis-cyclobutanediol.

[0058] Wherein, the cyclobutenedione has a structure shown in Formula II:

[0059]

[0060] The chiral cis-cyclobutanediol has a structure shown in Formula I, i.e., (1S, 2R, 3R, 4R)-cyclobutanediol:

[0061]

[0062] Among them, R 1 、R 2 、R 3 、R 4 、R 5 are each independently selected from hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroaryl, substituted heteroaryl, or a non-hydrocarbon group;

[0063] R 6 is selected from alkyl, substituted alkyl, heteroaryl, substituted heteroaryl or non-hydrocarbon groups.

[0064] In some embodiments, R 1 、R 2 、R 3 、R 4 、R 5 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;

[0065] R 6 Selected from C1-C 20 Alkyl, C1-C 20 Substituted alkyl, C5-C 20 Heteroaryl, C5-C 20 Substituted heteroaryl or non-hydrocarbon groups.

[0066] In some embodiments, R 1 、R 2 、R 3 、R 4 、R 5 Each independently selected from hydrogen, C1-C 10 Hydrocarbon, C1-C 10 substituted hydrocarbon or non-hydrocarbon groups;

[0067] R 6 Selected from C1-C 10 Alkyl, C1-C 10 Substituted alkyl or non-hydrocarbon groups.

[0068] In some embodiments, the substituents in the substituted alkyl, substituted hydrocarbon or substituted heteroaryl are each independently selected from C1-C 20 Hydrocarbon, C5-C 20 heteroaryl or non-hydrocarbon groups;

[0069] In some embodiments, the substituents in the substituted alkyl, substituted hydrocarbon or substituted heteroaryl are each independently selected from C1-C 10 Hydrocarbon, C5-C 10 Aryl, C5-C 10 Heteroaryl or non-hydrocarbon group.

[0070] 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):

[0071]

[0072]

[0073] M 31 -O- Formula (3)

[0074] Among them, M 11 、M 21 and M 31 independently selected from hydrogen or C1-C 10 alkyl.

[0075] In some embodiments, the non-hydrocarbon group includes oxygen, halogen, hydroxyl, C1-C 10 Carboxyl, C1-C 10 Ester group, C1-C 10 Alkoxy, C1-C10 acyloxy.

[0076] In some embodiments, the halogen includes F, Cl, Br, and I.

[0077] In some embodiments, R1 、R 2 、R 3 、R 4 、R 5 Each independently selected from hydrogen, C1-C 10 Alkyl, C1-C 10 Alkoxy or halogen;

[0078] R 6 Selected from C1-C 10 Alkyl or C1-C 10 The substituted alkyl group is a substituted alkyl group, wherein the substituent in the substituted alkyl group is selected from at least one of halogen and phenyl.

[0079] In some embodiments, R 1 、R 2 、R 3 、R 4 、R 5 Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy or halogen;

[0080] R 6 Selected from C1-C6 alkyl or C1-C6 substituted alkyl, wherein the substituent in the substituted alkyl is selected from at least one of halogen or phenyl.

[0081] 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;

[0082] R 6 is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, cyclohexyl, benzyl or phenethyl, and optionally, at least one hydrogen in the group is substituted by halogen.

[0083] In some embodiments, the chiral catalyst is selected from catalysts based on chiral metal complexes.

[0084] In some embodiments, the chiral catalyst is selected from at least one catalyst based on a chiral ruthenium (Ru) complex.

[0085] In some embodiments, the chiral catalyst is selected from at least one of the following catalysts C1-C11:

[0086]

[0087] In some preferred embodiments, the chiral catalyst is catalyst C5.

[0088] The inventors found that when the catalyst C5 is used, the yield of chiral cis-cyclobutanediol can reach more than 85%, and the enantiomeric excess (ee) is more than 90%.

[0089] In some embodiments, the Lewis acid compound is selected from at least one of lithium chloride, magnesium chloride, scandium chloride, zinc chloride, titanium tetrachloride, lithium trifluoromethanesulfonate, magnesium trifluoromethanesulfonate, scandium trifluoromethanesulfonate, zinc trifluoromethanesulfonate, and isopropyl titanate.

[0090] More preferably, the Lewis acid compound is lithium chloride.

[0091] In some embodiments, the molar ratio of the cyclobutenedione, the chiral catalyst, and the Lewis acid compound is 1:(0.03-0.05):(0.1-0.3).

[0092] In some embodiments, the molar ratio of the cyclobutenedione to the chiral catalyst is independently selected from any value among 1:0.031, 1:0.032, 1:0.033, 1:0.034, 1:0.035, 1:0.036, 1:0.037, 1:0.038, 1:0.039, 1:0.040, 1:0.041, 1:0.042, 1:0.043, 1:0.044, 1:0.045, 1:0.046, 1:0.047, 1:0.048, 1:0.049, 1:0.050, or any range therebetween.

[0093] In some embodiments, the molar ratio of the cyclobutenedione to the Lewis acid compound is independently selected from any value among 1:0.11, 1:0.12, 1:0.13, 1:0.14, 1:0.15, 1:0.16, 1:0.17, 1:0.18, 1:0.19, 1:0.20, 1:0.21, 1:0.22, 1:0.23, 1:0.24, 1:0.25, 1:0.26, 1:0.27, 1:0.28, 1:0.29, 1:0.30, or any range therebetween.

[0094] In some preferred embodiments, the molar ratio of the cyclobutenedione, the catalyst, and the Lewis acid compound is 1:(0.035-0.045):(0.15-0.25).

[0095] 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.

[0096] In some embodiments, the molar ratio of the transfer hydrogenation reagent to the cyclobutenedione is (5-20):1.

[0097] In some embodiments, the molar ratio of the transfer hydrogenation reagent to the cyclobutenedione 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.

[0098] In some preferred embodiments, the molar ratio of the transfer hydrogenation reagent to the cyclobutenedione is (8-15):1.

[0099] 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.

[0100] In some preferred embodiments, the transfer hydrogenation reagent is formic acid / tetramethylethylenediamine.

[0101] In some embodiments, in the formic acid / amine azeotrope, the volume ratio of formic acid to amine azeotrope is 5:2-6.

[0102] 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.

[0103] In some embodiments, the reaction system may further comprise a solvent, which may be another solvent different from the raw material cyclobutenedione and the transfer hydrogenation reagent.

[0104] In some embodiments, the solvent is selected from at least one of acetonitrile, dichloromethane, and ethyl acetate.

[0105] In some embodiments, the selective transfer hydrogenation reaction of cyclobutenedione of the present application can occur without the need for additional solvent.

[0106] In some embodiments, the reaction temperature is 5 to 40° C., and the reaction time is 2 to 8 hours.

[0107] In some embodiments, the reaction temperature is independently selected from any value of 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, or any range therebetween.

[0108] In some embodiments, the reaction time of the reaction is independently selected from any value among 2.0 h, 2.5 h, 3.0 h, 3.5 h, 4.0 h, 4.5 h, 5.0 h, 5.5 h, 6.0 h, 6.5 h, 7.0 h, 7.5 h, 8.0 h, or any range therebetween.

[0109] In some preferred embodiments, the reaction temperature is 10-35°C and the reaction time is 3-6 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.

[0110] In some embodiments, the method comprises the following steps:

[0111] A mixture comprising cyclobutenedione represented by formula II, a transfer hydrogenation reagent, a chiral catalyst and a Lewis acid compound is placed in a reaction vessel and stirred at 5 to 40° C. for 2 to 8 hours to perform a transfer hydrogenation reaction to obtain a reaction product represented by formula I.

[0112] In some embodiments, the method further comprises the step of separating and purifying the chiral cis-cyclobutanediol.

[0113] In some embodiments, the method comprises the following steps:

[0114] a) placing a mixture comprising a cyclobutenedione of formula II, a transfer hydrogenation reagent, a chiral catalyst, and a Lewis acid compound in a reaction vessel, stirring at 5 to 40° C. for 2 to 8 hours to perform the transfer hydrogenation reaction to obtain a reaction product;

[0115] b) extracting the reaction product and concentrating the obtained organic phase to obtain a crude product;

[0116] c) purifying the crude product by silica gel column chromatography to obtain purified chiral cis-cyclobutanediol.

[0117] In some embodiments, the extraction is performed using ethyl acetate.

[0118] In some embodiments, the concentrating comprises drying over anhydrous sodium sulfate and rotary evaporation.

[0119] In some embodiments, the concentrating is performed under reduced pressure.

[0120] In a specific embodiment, the transfer hydrogenation reaction is carried out at 10-35° C. with stirring for 3-6 hours.

[0121] The present application is described in detail below with reference to embodiments, but the present application is not limited to these embodiments.

[0122] Unless otherwise specified, the raw materials and reagents in the examples of this application were purchased through commercial channels.

[0123] The instruments used in the examples of this application are as follows:

[0124] 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.

[0125] The yield of chiral cis-cyclobutanediol is based on the amount of cyclobutenedione and is calculated by the following formula:

[0126] Yield % = (actual mass of target product obtained ÷ theoretical mass of target product) × 100%

[0127] The meanings of the abbreviations that may be involved in the examples of the present application are as follows: Me is methyl; Et is ethyl; HCOOH is formic acid; TMEDA is tetramethylethylenediamine; NMR is nuclear magnetic resonance; chiral HPLC is high performance liquid chromatography equipped with a chiral chromatographic column; ee value is the enantiomeric excess ratio value; dr represents the diastereomeric ratio; TLC is thin layer chromatography.

[0128] In the description of the embodiments of the present application, the amount of the catalyst is expressed as the molar percentage of the moles of the catalyst relative to the moles of cyclobutenedione; the amount of the Lewis acid compound is expressed as the molar percentage of the Lewis acid compound relative to cyclobutenedione; and the amount of the transfer hydrogenation reagent is expressed as the molar equivalent of the transfer hydrogenation reagent relative to cyclobutenedione.

[0129] Example 1

[0130]

[0131] 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 (18.6 mg, 0.1 mmol), Ru catalyst C5 (2.5 mg, 4 mol%), and lithium chloride (0.8 mg, 20 mol%) were added to the solution and stirred at 25°C for 4 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 = 5:1, v / v). The resulting product sample, designated 1-2, contained 19.0 mg of product with a yield of 99%, an ee value of 97%, and a dr ratio of 76:8:8:8.

[0132] The test data of product sample 1-2 are as follows:

[0133] Colorless oily liquid; 1 H NMR (400MHz, CDCl3) δ7.45(d,J=7.4Hz,2H),7.33(t,J=7.6Hz,2H),7.26-7.21(m,1H),4.59(t,J=6.0Hz,1H),4.49(t,J=5.4Hz,1 H),3.80-3.72(m,1H),2.64-2.55(m,1H),2.49(s,1H),2.33(s,1H),1.61-1.54(m,1H),1.38-1.27(m,1H),0.73(t,J=7.4Hz,3H). 13 C NMR(101MHz, CDCl3)δ136.3,131.0,128.4,126.6,70.1,68.7,48.6,42.8,17.5,12.9.HRMS(ESI-Quadrupole-Orbitrap)m / z:[M+Na] + Calcd for C 12 H 16 NaO2215.1043; Found:215.1041.[α] D 29 :+53.3 (c 0.3, CHCl3); HPLC analysis: 97%ee (Chiralcel IC, 10:90 i PrOH / hexanes, 1 mL / min, 220 nm), R t (major)=8.8min,R t (minor)=12.6min.IR(KBr thin film,cm-1 ):ν3734,3648,2359,2342,1684,1559,1540,1457,1275,1261.

[0134] Example 2

[0135]

[0136] A mixture of formic acid (38 μL, 10 equivalents) and tetramethylethylenediamine (120 μL, 8 equivalents) was dissolved in acetonitrile (0.5 mL). Cyclobutenedione 2-1 (20.0 mg, 0.1 mmol), Ru catalyst C5 (2.5 mg, 4 mol%), and lithium chloride (0.8 mg, 20 mol%) were added to the solution and stirred at 25°C for 4 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 = 5:1, v / v). The resulting product sample, designated 2-2, contained 19.8 mg of the product with a yield of 96%, an ee value of 96%, and a dr ratio of 72:14:12:4.

[0137] The test data of product sample 2-2 is as follows:

[0138] Colorless oily liquid; 1 H NMR (400MHz, CDCl3) δ7.45(d,J=7.5Hz,2H),7.33(t,J=7.5Hz,2H),7.28-7.22(m,1H),4.63-4.52(m,1H),4.47(d,J=0.5Hz,1H),3.79-3.72(m,1H) ,2.72-2.63(m,1H),2.53(d,J=3.9Hz,1H),2.35(d,J=7.0Hz,1H),1.60-1 .51(m,1H),1.31-1.16(m,2H),1.12-0.98(m,1H),0.78(t,J=7.1Hz,3H). 13 C NMR(151MHz, CDCl3)δ136.3,130.9,128.3,126.6,70.2,68.6,48.8,40.6,26.3,21.6,14.3.HRMS(ESI-Quadrupole-Orbitrap)m / z:[M+Na] + Calcd for C 13 H 18 NaO2 229.1199; Found:229.1197.[α] D20 :-66.7 (c 0.9, CHCl3); HPLC analysis: 96%ee (Chiralcel IA, 2:98 i PrOH / hexanes, 1 mL / min, 220 nm), R t (major)=14.8min,R t (minor)=13.1min.IR(KBr thin film,cm -1 ):ν3852,3734,2359,2342,1684,1558,1456,1275,1263,668.

[0139] Example 3

[0140]

[0141] A mixture of formic acid (38 μL, 10 equivalents) and tetramethylethylenediamine (120 μL, 8 equivalents) was dissolved in acetonitrile (0.5 mL). Cyclobutenedione 3-1 (23.4 mg, 0.1 mmol), Ru catalyst C5 (2.5 mg, 4 mol%), and lithium chloride (LiCl) (0.8 mg, 20 mol%) were added to the solution and stirred at 25°C for 4 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 = 5:1, v / v). The resulting product sample, designated 3-2, contained 21.6 mg of product with a yield of 90%, an ee value of 94%, and a dr ratio of 78:19:3:0.

[0142] The test data of product sample 3-2 are as follows:

[0143] Colorless oily liquid; 1 H NMR (600MHz, CDCl3) δ7.45-7.42(m,2H),7.35-7.32(m,2H),7.27-7.24(m,1H),4.63-4.59(m,1H),4.50-4.46(m,1H),3.78-3.73(m ,1H),3.39(t,J=6.5Hz,2H),2.73-2.63(m,1H),2.51(d,J=5.1Hz,1H),2.26(d,J=7.2Hz,1H),1.75-1.67(m,2H),1.52-1.40(m,2H). 13C NMR(151MHz, CDCl3)δ135.8,130.8,128.5,126.8,69.8,68.9,48.3,45.2,40.5,31.4,21.9.HRMS(ESI-Quadrupole-Orbitrap)m / z:[M+Na] + Calcdfor C 13 H 17 ClNaO2 263.0809; Found:263.0801.[α] D 29 :+40.0 (c 0.2, CHCl3); HPLC analysis: 94%ee (Chiralcel AD-H, 3:97 i PrOH / hexanes, 1 mL / min, 220 nm), R t (major)=17.1min,R t (minor)=15.1min.IR(KBr thin film,cm -1 ):ν33852,3734,2989,2360,2342,1558,1275,1261,703,668.

[0144] Example 4

[0145]

[0146] A mixture of formic acid (38 μL, 10 equivalents) and tetramethylethylenediamine (120 μL, 8 equivalents) was dissolved in acetonitrile (0.5 mL). Cyclobutenedione 4-1 (26.2 mg, 0.1 mmol), Ru catalyst C5 (2.5 mg, 4 mol%), and lithium chloride (LiCl) (0.8 mg, 20 mol%) were added to the solution and stirred at 25°C for 4 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 = 5:1, v / v). The resulting product sample, designated 4-2, contained 24.5 mg of product with a yield of 91%, an ee value of 92%, and a dr ratio of 88:4:4:4.

[0147] The test data of product sample 4-2 are as follows:

[0148] Colorless oily liquid; 11H NMR (400 MHz, CDCl3) δ 7.49 - 7.43 (m, 2H), 7.38 - 7.30 (m, 2H), 7.28 - 7.19 (m, 3H), 7.16 - 7.11 (m, 1H), 7.01 (d, J = 7.1 Hz, 2H), 4.57 (t, J = 6.0 Hz, 1H), 4.45 - 4.38 (m, 1H), 3.86 - 3.67 (m, 1H), 2.73 - 2.60 (m, 1H), 2.47 - 2.30 (m, 4H), 1.94 - 1.81 (m, 1H), 1.66 - 1.56 (m, 1H). 13 13C NMR (151 MHz, CDCl3) δ 142.6, 136.1, 131.0, 128.50, 128.45, 128.4, 126.8, 125.8, 70.3, 68.4, 49.0, 40.0, 34.4, 26.3. HRMS (ESI - Quadrupole - Orbitrap) m / z: [M + Na] + Calcd for C 18 H 20 NaO2 291.1356; Found: 291.1347. [α] D 20 : +43.9 (c 0.2, CHCl3); HPLC analysis: 92% ee (Chiralcel OD - H, 3:97 i PrOH / hexanes, 1 mL / min, 220 nm), R t (major) = 48.4 min, R t (minor) = 33.1 min. IR (KBr thin film, cm -1 ): ν 3852, 3735, 2928, 2359, 2342, 1683, 1540, 1506, 1275, 1261.

[0149] Example 5

[0150]

[0151] A mixture of formic acid (38 μL, 10 equivalents) and tetramethylethylenediamine (120 μL, 8 equivalents) was dissolved in acetonitrile (0.5 mL). Cyclobutenedione 5-1 (24.0 mg, 0.1 mmol), Ru catalyst C5 (2.5 mg, 4 mol%), and lithium chloride (0.8 mg, 20 mol%) were added to the solution and stirred at 25°C for 4 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 = 5:1, v / v). The resulting product sample, designated 5-2, contained 20.9 mg of product with an 85% yield, 99% ee, and a 76:0:14:10 dr ratio.

[0152] The test data of product sample 5-2 are as follows:

[0153] Colorless oily liquid; 1 H NMR (600MHz, CDCl3) δ7.36-7.32(m,2H),7.25-7.21(m,3H),4.32(d,J=6.7Hz,1H),4.25-4.20(m,1H),3.52(t,J=7.7Hz,1H),2.53-2.45(m,1H),1.9 7-1.91(m,1H),1.88(s,1H),1.71-1.60(m,5H),1.44(d,J=5.4Hz,1H),1. 31-1.19(m,2H),1.18-1.11(m,1H),1.01-0.92(m,1H),0.83-0.75(m,1H). 13 C NMR(151MHz, CDCl3)δ138.3,128.80,128.75,126.9,75.1,74.6,46.5,45.6,37.5,32.6,30.8,26.7,26.3,26.1.HRMS(ESI-Quadrupole-Orbitrap)m / z:[M+Na] + Calcd for C 16 H 22 NaO2269.1512; Found:269.1506.[α] D 20 :+25.8 (c 0.1, CHCl3); HPLC analysis: 99%ee (Chiralcel OD-H, 5:95 i PrOH / hexanes, 1 mL / min, 220 nm), R t(major)=7.2min,R t (minor)=11.1min.IR(KBr thin film,cm -1 ):ν3852,3734,2929,2359,2342,1558,1511,1275,1260,1038,668.

[0154] Example 6

[0155]

[0156] A mixture of formic acid (38 μL, 10 equivalents) and tetramethylethylenediamine (120 μL, 8 equivalents) was dissolved in acetonitrile (0.5 mL). Cyclobutenedione 6-1 (21.4 mg, 0.1 mmol), Ru catalyst C5 (2.5 mg, 4 mol%), and lithium chloride (LiCl) (0.8 mg, 20 mol%) were added to the solution and stirred at 25°C for 4 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 = 5:1, v / v). The resulting product sample, designated 6-2, contained 19.7 mg of product with an 89% yield, 97% ee, and a 78:11:11:0 dr ratio.

[0157] The test data of product sample 6-2 are as follows:

[0158] Colorless oily liquid; 1 H NMR (600MHz, CDCl3) δ7.37-7.32(m,2H),7.15(d,J=8.2Hz,2H),4.58-4.53( m,1H),4.47(dd,J=9.7,4.8Hz,1H),3.76-3.69(m,1H),2.62(q,J=7.6Hz,2H ),2.59-2.53(m,1H),2.43(d,J=4.9Hz,1H),2.22(d,J=7.3Hz,1H),1.62-1. 59(m,1H),1.34-1.29(m,1H),1.22(t,J=7.6Hz,3H),0.73(t,J=7.4Hz,3H). 13 C NMR(151MHz, CDCl3)δ142.5,133.2,130.8,127.9,70.0,68.6,48.2,42.7,28.5,17.5,15.6,12.9.HRMS(ESI-Quadrupole-Orbitrap)m / z:[M+Na] +Calcd for C 14 H 20 NaO2 243.1356; Found:243.1355.[α] D 20 :+25.2 (c 0.35, CHCl3); HPLC analysis: 97%ee (Chiralcel AD-H, 3:97 i PrOH / hexanes, 1 mL / min, 220 nm), R t (major) = 9.0 min, R t (minor)=8.0min.IR(KBr thin film,cm -1 ):ν3734,3648,2359,2342,1684,1653,1558,1275,1260.920.

[0159] Example 7

[0160]

[0161] A mixture of formic acid (38 μL, 10 equivalents) and tetramethylethylenediamine (120 μL, 8 equivalents) was dissolved in acetonitrile (0.5 mL). Cyclobutenedione 7-1 (24.4 mg, 0.1 mmol), Ru catalyst C5 (2.5 mg, 4 mol%), and lithium chloride (LiCl) (0.8 mg, 20 mol%) were added to the solution and stirred at 25°C for 4 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 = 5:1, v / v). The resulting product sample, designated 7-2, contained 23.1 mg of product with a yield of 92%, an ee value of 93%, and a dr ratio of 78:5:10:7.

[0162] The test data of product sample 7-2 is as follows:

[0163] Colorless oily liquid; 11H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 4.53 (s, 1H), 4.46 - 4.44 (m, 1H), 3.80 (s, 3H), 3.76 - 3.68 (m, 1H), 2.67 - 2.56 (m, 1H), 2.51 (s, 1H), 2.31 (d, J = 2.0 Hz, 1H), 1.59 - 1.48 (m, 1H), 1.32 - 1.25 (m, 1H), 1.23 - 1.10 (m, 3H), 1.03 - 0.93 (m, 1H), 0.77 (t, J = 7.1 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 158.3, 132.0, 128.1, 113.7, 70.4, 68.3, 55.2, 48.3, 40.5, 30.5, 23.6, 22.7, 14.0. HRMS (ESI - Quadrupole - Orbitrap) m / z: [M+Na] + Calcd for C 15 H 22 NaO3 273.1461; Found: 273.1460. [α] D 20 : +55.34 (c 0.2, CHCl3); HPLC analysis: 93% ee (Chiralcel AD - H, 2:98 i PrOH / hexanes, 1 mL / min, 220 nm), R t (major) = 22.3 min, R t (minor) = 20.2 min. IR (KBr thin film, cm -1 ): ν 3852, 3648, 2928, 2359, 2342, 1511, 1457, 1275, 1260, 1181, 1038, 668.

[0164] Example 8

[0165]

[0166] A mixture of formic acid (38 μL, 10 equivalents) and tetramethylethylenediamine (120 μL, 8 equivalents) was dissolved in acetonitrile (0.5 mL). Cyclobutenedione 8-1 (32.0 mg, 0.1 mmol), Ru catalyst C5 (2.5 mg, 4 mol%), and lithium chloride (0.8 mg, 20 mol%) were added to the solution and stirred at 25°C for 4 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 = 5:1, v / v). The resulting product sample, designated 8-2, contained 29.1 mg of product with an 89% yield, 95% ee, and a dr ratio of 89:11:0:0.

[0167] The test data of product sample 8-2 are as follows:

[0168] Colorless oily liquid; 1 H NMR (600MHz, CDCl3) δ7.62(s,1H),7.447.34(m,2H),7.19(t,J=7.8Hz,1H),4.58(d,J=4.9Hz,1H),4.48(s,1H),3.70(t,J=8.2 Hz,1H),2.72-2.58(m,1H),2.52-2.37(m,2H),1.58-1.45(m,1H),1.31-1.08(m,8H),1.05-0.90(m,1H),0.82(t,J=6.9Hz,3H). 13 C NMR (101MHz, CDCl3) δ137.9,132.7,128.6,128.50,128.47,121.3,69.2,67.4,47.6,3 9.6,30.6,28.2,27.1,22.8,21.5,13.0.HRMS(ESI-Quadrupole-Orbitrap)m / z:[M+Na] + Calcd for C 16 H 23 BrNaO2 349.0774; Found:349.0769.[α] D 20 :+51.1 (c 0.75, CHCl3); HPLC analysis: 95%ee (Chiralcel OJ-H, 2:98 i PrOH / hexanes, 1 mL / min, 220 nm), R t (major)=12.1min,R t(minor)=10.2min.IR(KBr thin film,cm -1 ):ν3852,3734,2359,2342,1558,1506,1472,1275,1260,668.

[0169] Example 9

[0170]

[0171] 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 (18.6 mg, 0.1 mmol), Ru catalyst C5 (2.5 mg, 4 mol%), and lithium chloride (0.8 mg, 20 mol%) were added to the solution and stirred at 25°C for 4 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 = 5:1, v / v). The resulting product sample, designated 1-2, contained 18.6 mg of product with a yield of 97%, an ee value of 96%, and a dr ratio of 50:17:17:16.

[0172] Example 10

[0173]

[0174] 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 (18.6 mg, 0.1 mmol), Ru catalyst C5 (2.5 mg, 4 mol%), and copper trifluoromethanesulfonate (Cu(OTf)2) (7.2 mg, 20 mol%) were added to the solution and stirred at 25°C for 4 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 = 5:1, v / v). The resulting product sample, designated 1-2, contained 19.0 mg of product with a yield of 99%, an ee value of 97%, and a dr ratio of 50:17:17:16.

[0175] 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-cyclobutanediol, characterized in that: include: In the presence of a chiral catalyst, a Lewis acid compound and a transfer hydrogenation reagent, cyclobutenedione is subjected to a selective transfer hydrogenation reaction to generate chiral cis-cyclobutanediol. Wherein, the cyclobutenedione has a structure shown in Formula II: The chiral cis-cyclobutanediol has a structure shown in Formula I: Among them, R 1 、R 2 、R 3 、R 4 、R 5 are each independently selected from hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroaryl, substituted heteroaryl, or a non-hydrocarbon group; R 6 is selected from alkyl, substituted alkyl, heteroaryl, substituted heteroaryl or non-hydrocarbon groups.

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

3. The method according to claim 1, characterized in that The substituents in the substituted alkyl, substituted hydrocarbon or substituted heteroaryl are each independently selected from C1-C 20 Hydrocarbon, C5-C 20 heteroaryl 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 or C1-C 10 The substituted alkyl group is a substituted alkyl group, wherein the substituent in the substituted alkyl group is selected from at least one of halogen and phenyl.

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:

6. The method according to claim 1, characterized in that The Lewis acid compound is at least one selected from lithium chloride, magnesium chloride, scandium chloride, zinc chloride, titanium tetrachloride, lithium trifluoromethanesulfonate, magnesium trifluoromethanesulfonate, scandium trifluoromethanesulfonate, zinc trifluoromethanesulfonate, and isopropyl titanate; Preferably, the molar ratio of the cyclobutenedione, the chiral catalyst and the Lewis acid compound is 1:(0.03-0.05):(0.1-0.3); Preferably, the molar ratio of the cyclobutenedione, the catalyst and the Lewis acid compound is 1:(0.035-0.045):(0.15-0.25).

7. 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, and formic acid / triethylamine; Preferably, the molar ratio of the transfer hydrogenation reagent to the cyclobutenedione is (5-20):1; preferably (8-15):

1.

8. The method according to claim 1, characterized in that The reaction temperature of the reaction is 5 to 40°C, and the reaction time is 2 to 8 hours; Preferably, the reaction temperature is 10-35° C., and the reaction time is 3-6 h.

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

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, the chiral catalyst, and the Lewis acid compound in a reaction vessel, stirring at 5 to 40° C. for 2 to 8 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-cyclobutanediol.

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