Biphenyl axial chiral medium-macrocyclic compound and synthesis method thereof

Abstract

The invention belongs to the field of organic chemistry, and relates to a biphenyl axially chiral medium-macrocyclic compound and a synthesis method thereof. The biphenyl axially chiral middle-macrocyclic compound is a middle-ring lactone compound, a macrocyclic compound synthesized between the middle-ring lactone compounds, or a macrocyclic compound synthesized between the middle-ring lactone compounds and a second reaction substrate; wherein the middle ring lactone compound is shown as a formula (I): # imgabs0 # formula (I), in the formula (I), R1 to R3 are respectively and independently hydrogen, C1-C5 alkyl or C6-C10 aryl, or R1 and R2 form a C3-C8 ring or form naphthyl together with substituted phenyl of the C3-C8 ring; and R4 is selected from at least one of hydrogen, alkyl groups of C1-C5, alkoxy groups of C1-C5, halogen, aryl groups of C6-C10, alkynyl groups of C3-C10, ester groups of C3-C6 and biboric acid ester groups. The synthesis of the 10-membered middle ring lactone compound and the axially chiral macrocyclic compound taking the 10-membered middle ring lactone compound as a reaction substrate is realized.

Description

Technical Field

[0001] The invention belongs to the field of organic chemistry, and in particular relates to a biphenyl axial chiral meso-macrocyclic compound and a synthesis method thereof. Background Art

[0002] Macrocyclic compounds usually refer to cyclic molecules with 12 or more atoms. They have important applications in the field of medicine and have unique advantages. They can provide functional diversity and stereochemical complexity. Compared with open-ring analogs, macrocyclic compounds have higher affinity and selectivity and can bind to targets that are difficult to act on with traditional small molecule drugs. In recent years, the interest in macrocyclic compounds in different scientific fields has also been growing year by year. Among them, the number of articles searched with the keywords "macrocycle" and "macrocycle and drug discovery" counted by the US National Library of Medicine has increased year by year. However, the asymmetric synthesis of macrocyclic compounds is rarely reported. The key scientific problem is that the synthesis of macrocyclic compounds is difficult and the reaction conditions are harsh. Regarding the synthesis of chiral macrocycles, there are currently two main strategies: one is to start from a linear substrate for intramolecular cyclization, and the other is to start from a racemic macrocycle for functionalization. Only recently have there been a few cases of direct intermolecular synthesis of chiral macrocycles starting from two substrates. However, most of them have problems such as low reaction efficiency and insufficient structural diversity. Summary of the invention

[0003] In order to solve the above problems existing in the prior art, the present invention provides a biphenyl axial chiral medium macrocyclic compound and a synthesis method thereof, and utilizes the torsional tension characteristics of 6-membered biaryl lactone to cause an asymmetric (6+4) cyclization reaction with tert-butyl carbonate compounds under the action of a palladium catalyst, thereby constructing a series of CC axial chiral 10-membered medium-ring lactone compounds, and the reaction has good yield and excellent chemical selectivity. Moreover, on this basis, we utilize the mechanism of ring tension release step by step, and then respectively react with axial chiral 10-membered medium-ring lactone, benzofuranone-derived imine, enone intermediate and γ-butyrolactone-derived cyclopropane to achieve the synthesis of a series of axial chiral macrocyclic compounds.

[0004] In order to achieve the above-mentioned object, the first aspect of the present invention provides a biphenyl axial chiral medium macrocyclic compound, wherein the biphenyl axial chiral medium macrocyclic compound is a medium ring lactone compound, a macrocyclic compound synthesized by a dipolar cyclization reaction between medium ring lactone compounds, or a macrocyclic compound synthesized by a dipolar cyclization reaction between a medium ring lactone compound and a second reaction substrate; the second reaction substrate is selected from at least one of a benzofuranone-derived imine, a diazo compound enone intermediate, or a γ-butyrolactone-derived cyclopropane;

[0005] Wherein, the mesocyclic lactone compound is as shown in formula (I):

[0006]

[0007] In formula (I), R 1 -R 3 are each independently hydrogen, C1-C5 alkyl or C6-C10 aryl, or R 1 , R 2 Form a C3-C8 ring or form a naphthyl group together with the phenyl group substituted by it; R 4 At least one selected from hydrogen, C1-C5 alkyl, C1-C5 alkoxy, halogen, C6-C10 aryl, C3-C10 alkynyl, C3-C6 ester and biboric acid ester.

[0008] The second aspect of the present invention provides a method for synthesizing the biphenyl axial chiral macrocyclic compound, comprising the following steps:

[0009] Step (a): Under the protection of a second inert gas, dissolving the six-membered biaryl lactone compound represented by formula (5), the tert-butyl carbonate compound represented by formula (6), the first catalyst and the first chiral ligand in a second solvent, and performing an asymmetric cyclization reaction to obtain the medium-ring lactone compound;

[0010]

[0011] R in formula (5) 1 -R 4 With R in formula (I) 1 -R 4 The definitions are the same;

[0012] and optionally step (b);

[0013] Step (b): subjecting the mesocyclic lactone compounds to a dipolar cyclization reaction, or subjecting the mesocyclic lactone compound to a dipolar cyclization reaction with a second reaction substrate, to obtain the biphenyl axial chiral macrocyclic compound.

[0014] The present invention has the following advantages:

[0015] The present invention utilizes the torsional tension property of 6-membered biaryl lactone to cause an asymmetric (6+4) cyclization reaction between the 6-membered biaryl lactone and tert-butyl carbonate compounds under the action of a palladium catalyst, thereby constructing a series of CC axially chiral 10-membered medium-ring lactone compounds. The reaction has good yield and excellent chemical selectivity, and the 10-membered medium-ring lactone compound is used as a reaction substrate to achieve the synthesis of a series of axially chiral macrocyclic compounds. The synthesis method has simple steps, mild conditions, high yield and high enantiomeric selectivity.

[0016] Other features and advantages of the present invention will be described in detail in the following detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] The above and other objects, features and advantages of the present invention will become more apparent through a more detailed description of exemplary embodiments of the present invention in conjunction with the accompanying drawings, wherein like reference numerals generally represent like components throughout the exemplary embodiments of the present invention.

[0018] Figure 1 The main chiral 20-membered ring II-1 is mixed with the guest (R)-prolinol and (S)-prolinol in equal moles. 1 H NMR spectra.

[0019] Figure 2 The main chiral 20-membered ring II-1 is mixed with the guest (R,R)-cyclohexanediamine and (S,S)-cyclohexanediamine in equal moles. 1 H NMR spectra. DETAILED DESCRIPTION

[0020] The preferred embodiments of the present invention will be described in more detail below. Although the preferred embodiments of the present invention are described below, it should be understood that the present invention can be implemented in various forms and should not be limited to the embodiments set forth herein.

[0021] In order to achieve the above-mentioned object, the first aspect of the present invention provides a biphenyl axial chiral medium macrocyclic compound, wherein the biphenyl axial chiral medium macrocyclic compound is a medium ring lactone compound, a macrocyclic compound synthesized by a dipolar cyclization reaction between medium ring lactone compounds, or a macrocyclic compound synthesized by a dipolar cyclization reaction between a medium ring lactone compound and a second reaction substrate; the second reaction substrate is selected from at least one of a benzofuranone-derived imine, a diazo compound enone intermediate, or a γ-butyrolactone-derived cyclopropane;

[0022] Wherein, the mesocyclic lactone compound is as shown in formula (I):

[0023]

[0024] In formula (I), R 1 -R 3 are each independently hydrogen, C1-C5 alkyl or C6-C10 aryl, or R 1 , R 2 Form a C3-C8 ring or form a naphthyl group together with the phenyl group substituted by it; R 4 At least one selected from hydrogen, C1-C5 alkyl, C1-C5 alkoxy, halogen, C6-C10 aryl, C3-C10 alkynyl, C3-C6 ester and biboric acid ester.

[0025] According to the present invention, preferably, R 1 -R2 is hydrogen, R 3 is ethyl or phenyl; or, R 2 -R 3 is hydrogen, R 1 is methyl, ethyl, n-propyl or n-butyl; or, R 3 is hydrogen, R 1 , R 2 Form a C4 ring, a C5 ring, or form a naphthyl group together with the phenyl group substituted therewith;

[0026] R 4 is hydrogen, 3-methoxy, 3-methyl, 3-ethyl, 3-benzyl, 3-bromo, 3-phenyl, 3-isopropenyl, 4-methyl, 4-phenyl, 4-bromo, 4-borate, 4-phenylethynyl or 4-ester.

[0027] According to the present invention, preferably, the structural formulas of the benzofuranone-derived imine, the diazo compound enone intermediate and the γ-butyrolactone-derived cyclopropane are respectively as shown in formula (1) to formula (3):

[0028]

[0029] In formula (2), R 5 is a C6-C10 aryl group, a halogen-substituted C6-C10 aryl group or a naphthyl group, preferably a phenyl group, a 4-chlorophenyl group or a 2-naphthyl group;

[0030] In formula (3), R 6 It is a C6-C10 aryl group, a halogen-substituted C6-C10 aryl group or a naphthyl group, and is preferably a phenyl group, a 4-chlorophenyl group, a 4-methylphenyl group or a 2-naphthyl group.

[0031] According to the present invention, preferably, the macrocyclic compound is selected from at least one of the compounds represented by formula (II) to formula (V);

[0032]

[0033] R in formula (II) to formula (V) 1 -R 4 With R in formula (I) 1 -R 4 The definition is the same, R 5 With R in formula (2) 5 The definition is the same, R 6 With R in formula (3) 6 The definitions are the same;

[0034] Preferably, in formula (II), R 2 -R 3 is hydrogen, R 1 is methyl or n-propyl; or, R1 -R 2 is hydrogen, R 3 is phenyl; R 4 is hydrogen, 3-methyl, 3-benzyl, 3-bromo or 4-bromo;

[0035] Preferably, in formula (III), R 2 -R 3 is hydrogen, R 1 is methyl; or, R 1 -R 2 is hydrogen, R 3 is phenyl; R 4 is hydrogen or 4-bromo;

[0036] Preferably, in formula (IV), R 2 -R 3 is hydrogen, R 1 is methyl, R 4 is hydrogen;

[0037] Preferably, in formula (V), R 2 -R 3 is hydrogen, R 1 is methyl, R 4 It is hydrogen or 3-bromo.

[0038] According to the present invention, preferably, the diazo compound enone intermediate is an enone produced by Wollf rearrangement of a diazo compound under light conditions; the diazo compound is as shown in formula (4);

[0039]

[0040] R in formula (4) 5 With R in formula (2) 5 The definition is the same.

[0041] According to the present invention, preferably, the diazo compound ketene intermediate is prepared by a preparation method comprising the following steps:

[0042] Under the protection of a first inert gas and in the presence of a first solvent, the diazo compound is subjected to light treatment to obtain the diazo compound enone intermediate;

[0043] Preferably, the first inert gas is argon and / or nitrogen; the first solvent is dichloromethane; the light treatment uses visible light, the wavelength of the visible light is 350-400nm, the light intensity is 8-15W, the light temperature is 0-40°C, and the light time is 2-6h.

[0044] The second aspect of the present invention provides a method for synthesizing the biphenyl axial chiral macrocyclic compound, comprising the following steps:

[0045] Step (a): Under the protection of a second inert gas, dissolving the six-membered biaryl lactone compound represented by formula (5), the tert-butyl carbonate compound represented by formula (6), the first catalyst and the first chiral ligand in a second solvent, and performing an asymmetric cyclization reaction to obtain the medium-ring lactone compound;

[0046]

[0047] R in formula (5) 1 -R 4 With R in formula (I) 1 -R 4 The definitions are the same;

[0048] and optionally step (b);

[0049] Step (b): allowing the mesocyclic lactone compounds to undergo a dipolar cyclization reaction, or allowing the mesocyclic lactone compound to undergo a dipolar cyclization reaction with a second reaction substrate, to obtain the biphenyl axial chiral macrocyclic compound.

[0050] According to the present invention, preferably, in step (a), the first catalyst is tris(dibenzylideneacetone)dipalladium chloroform adduct and / or tris(dibenzylideneacetone)dipalladium;

[0051] The first chiral ligand is a compound having a structure represented by formula (7) or a compound having a structure represented by formula (8);

[0052]

[0053] The second solvent is toluene and / or o-xylene;

[0054] The second inert gas is argon and / or nitrogen;

[0055] The molar ratio of the hexaaryl lactone compound, the tert-butyl carbonate compound, the chiral ligand and the first catalyst is 1:1.5-2.0::0.12-0.15:0.05-0.06;

[0056] The temperature of the asymmetric cyclization reaction is 10-20°C.

[0057] According to the present invention, preferably, in step (b), the dipolar cyclization reaction between the mesocyclic lactone compounds comprises:

[0058] Under the protection of a third inert gas, one or two mesocyclic lactone compounds, a second catalyst and a second chiral ligand are dissolved in a third solvent to carry out a dipolar cyclization reaction to obtain the biphenyl axial chiral macrocyclic compound;

[0059] Preferably, the second catalyst is tris(dibenzylideneacetone)dipalladium chloroform adduct and / or tris(dibenzylideneacetone)dipalladium; the second chiral ligand is a compound having a structure shown in formula (7) or a compound having a structure shown in formula (8);

[0060]

[0061] Preferably, the third inert gas is argon and / or nitrogen; the third solvent is at least one of 1,4-dioxane and / or tetrahydrofuran; the molar ratio of the total amount of the mesocyclic lactone compound, the second chiral ligand and the second catalyst is 1:0.12-0.15:0.05-0.06;

[0062] Preferably, the conditions of the dipolar cyclization reaction include: temperature of 0 to 40° C. and time of 2 to 10 h.

[0063] According to the present invention, preferably, in step (b), the dipolar cyclization reaction between the mesocyclic lactone compound and the second reaction substrate comprises:

[0064] Under the protection of a fourth inert gas, dissolving the mesocyclic lactone compound, the second reaction substrate and the third catalyst in a fourth solvent to undergo a dipolar cyclization reaction to obtain the biphenyl axial chiral macrocyclic compound;

[0065] Preferably, the fourth inert gas is argon and / or nitrogen; the third catalyst is Pd(PPh3)4 and / or tris(dibenzylideneacetone)dipalladium; the fourth solvent is dichloromethane and / or 1,2-dichloroethane; the molar ratio of the medium-ring lactone compound, the second reaction substrate and the third catalyst is 1:3-4:0.1-0.12;

[0066] Preferably, the conditions of the dipolar cyclization reaction include: temperature of 0 to 40° C. and time of 2 to 10 h.

[0067] Example 1

[0068] Preparation of Compound I-1

[0069]

[0070] Under argon atmosphere, 5 mol% Pd2(dba)3·CHCl3 and chiral ligand and 1 mL of anhydrous toluene were added to a dry Schlenk reaction tube, stirred at room temperature for 30 minutes, and then the substrate Sub1 (0.1 mmol, 1.0 equiv.), Sub2 (0.15 mmol, 1.5 equiv.) and 1 mL of anhydrous toluene were added, and reacted at 15°C for 24 hours. The 10-membered ring compound 1 (27.4 mg, isolated yield: 83%) was obtained by column chromatography (PE: EtOAc = 10: 1), and the enantiomeric excess value (90% ee) of the purified product was determined by chiral HPLC.

[0071] 1 H NMR (400MHz, CDCl3) δ7.85-7.77(m,2H),7.51-7.47(m,1H),7.45-7.37(m,2H),7.37-7.26(m,4H), 5.35-5.27(m,2H),5.00(d,J=12.4Hz,1H),4.91-4.80(m,2H),4.73(d,J=12.4Hz,1H),1.91(s,3H).

[0072] 13 C NMR (100 MHz, CDCl 3) δ152.2,138.9,138.4,133.0,132.9,132.4,129.3,129.1,128.2,127.3,126.8,125.0,124.0,123.7,121.7,116.2,72.8,67.8,20.9.

[0073] Chiral HPLC: Chiral AZ column, V 正己烷 / V 异丙醇 =95:5, flow rate 1.0mL / min, λ=254nm

[0074] tR(major)=29.83min, tR(minor)=28.19min.

[0075] High resolution: Calculated value: [M+Na] + :353.1148, measured value:353.1145.

[0076] Optical rotation: [α] D 25 =-155.33 (c = 1.00 in CHCl3)

[0077] Examples I-1 to I-22

[0078] The compounds listed in Table 1 were prepared according to the method of Example 1, except that the substrate Sub 1 was replaced by Sub 1-X listed in Table 1.

[0079]

[0080]

[0081]

[0082]

[0083]

[0084] Example 2

[0085] Preparation of compound II-1

[0086]

[0087] Under argon atmosphere, 5 mol% Pd2(dba)3·CHCl3 and chiral ligand L and 1 mL of anhydrous 1,4-dioxane were added to a dry Schlenk reaction tube, stirred at room temperature for 30 minutes, and then 10-membered ring compound 1 (0.05 mmol, 1.0 equiv.) and 1 mL of anhydrous 1,4-dioxane were added, and reacted at 30°C for 4 hours. Column chromatography (PE: EtOAc = 15: 1) gave 20-membered ring compound 2 (30.7 mg, isolation yield: 93%). 1 The dr value was determined by H NMR spectrum, and the enantiomeric excess (ee value) of the purified product was determined by chiral HPLC. The results showed 99% ee, 10:1 dr.

[0088] 1 H NMR (400MHz, CDCl3) δ7.96-7.82(m,3H),7.48-7.27(m,4H),7.20-7.12(m,2H),4.64(s,1H), 4.55(s,1H),4.12(d,J=7.3Hz,1H),4.10-3.98(m,2H),3.66(d,J=12.5Hz,1H),1.84(s,3H).

[0089] 13C NMR (100MHz, CDCl3) δ167.7,151.8,139.2,138.8,135.9,133.6,133.1,131.7,129. 2,128.6,128.5,127.8,127.4,126.6,124.4,123.7,116.2,115.3,69.0,64.9,20.1.

[0090] Chiral HPLC: Chiral AZ column, V 正己烷 / V 异丙醇 =90:10, flow rate 1.0mL / min, λ=254nm

[0091] tR(major)=20.76min, tR(minor)=17.64min.

[0092] High resolution: Calculated value: [M+Na] + :683.2404, measured value:683.2404.

[0093] Optical rotation: [α] D 25 =85.27 (c = 1.00 in CHCl3)

[0094] Example 3

[0095] Preparation of compound III-1

[0096]

[0097] Under argon atmosphere, 10 mol% Pd(PPh3)4, 10-membered ring compound 1 (0.075 mmol, 1.5 equiv.), Sub3 (0.05 mmol, 1.0 equiv.) and 2 mL of anhydrous dichloromethane were added to a dry Schlenk reaction tube. The reaction was carried out at 30°C for 2 hours. Column chromatography (PE: EtOAc = 10: 1) was used to obtain 14-membered ring compound 3 (23.6 mg, isolated yield: 67%). 1 The dr value was determined by H NMR spectrum, and the enantiomeric excess (ee value) of the purified product was determined by chiral HPLC. The results showed 92% ee, >19:1 dr.

[0098] 1H NMR (400MHz, CDCl3) δ8.00-7.92(m,2H),7.86-7.81(m,1H),7.65(d,J=8.0Hz,2H),7.60(d, J=6.7Hz,2H),7.52-7.46(m,2H),7.43-7.37(m,2H),7.36-7.26(m,5H),7.15-7.25(m,5H), 7.06(s,1H),6.88(t,J=7.5Hz,1H),6.20(d,J=7.8Hz,1H),5.00(d,J=14.8Hz,1H),4.64(d, J=9.9Hz,2H),4.60(s,1H),4.26(s,1H),3.75(d,J=13.4Hz,1H),2.43(s,3H),1.95(s,3H).

[0099] 13 C NMR (100MHz, CDCl3) δ165.1,155.3,154.0,152.2,144.1,138.8,137.1,136.4,136.3,133.8,132.4,131.7,129.9,129.6,129.4,128.4,128.3, 128.0,127.7,127.4,127.0,126.6,125.1,124.5,124.1,123.8,122.7, 122.6,119.0,117.2,116.0,115.8,112.7,69.0,67.4,52.5,21.6,20.5.

[0100] Chiral HPLC: Chiral AZ column, V 正己烷 / V 异丙醇 =70:30, flow rate 1.0mL / min, λ=254nm

[0101] tR(major)=20.23min, tR(minor)=23.96min.

[0102] High resolution: Calculated value: [M+Na] + :728.2077, measured value:728.2071.

[0103] Optical rotation: [α] D 25 =12.47 (c = 0.80 in CHCl3).

[0104] Example 4

[0105] Preparation of compound IV-1

[0106]

[0107] Under argon atmosphere, Sub3 (0.15mmol, 3equiv.) and 1mL of anhydrous dichloromethane were added to a dry Schlenk reaction tube. At room temperature, the reaction was carried out under 6W blue light for 5 hours to obtain the intermediate Int1. In another dry Schlenk reaction tube, an argon atmosphere was maintained, and the ten-membered ring compound 1 (0.05mmol, 1.0equiv.), the obtained intermediate Int1 solution, 1mL of anhydrous dichloromethane and Pd(PPh3)4 (0.005mmol, 0.1equiv.) were added to the reaction system in sequence. The reaction was carried out at 30°C for 2 hours. The target product (24.9mg, separation yield: 84%) was obtained by column chromatography (PE:EtOAc=20:1). 1 The dr value was determined by H NMR spectrum, and the enantiomeric excess (ee value) of the purified product was determined by chiral HPLC. The results showed 92% / 88% ee, 3:1 dr.

[0108] Major+Minor: 1 H NMR (400MHz, CDCl3) δ8.18 (d, J=7.9Hz, 1H,

[0109] major), 7.93 - 7.81 (m, 3H, major + minor), 7.57 (d, J = 7.6 Hz, 1H, major), 7.49 (d, J = 7.6 Hz, 1H, minor), 7.46 - 7.30 (m, 7H, major + minor), 7.27 - 7.19 (m, 6H, major + minor), 7.18 - 7.11 (m, 3H, major + minor), 7.07 - 6.95 (m, 3H, minor), 6.89 - 6.80 (m, 2H, major + minor), 4.96 (s, 1H, minor), 4.88 (s, 1H, minor), 4.77 (s, 2H, major), 4.65 (d, J = 13.9 Hz, 1H, major), 4.49 (d, J = 13.7 Hz, 1H, major + minor), 3.18 (d, J = 14.3 Hz, 1H, minor), 3.00 (d, J = 14.3 Hz, 1H, major), 2.65 (d, J = 14.4 Hz, 1H, minor), 2.46 (d, J = 14.2 Hz, 1H, major), 1.93 (s, 6H, major), 1.83 (s, 3H, minor), 1.75 (s, 3H, minor), 1.63 (s, 3H, minor), 1.34 (s, 3H, major).

[0110] Major + Minor: 13 13C NMR (100 MHz, CDCl3) δ 172.6, 172.0, 163.8, 163.3, 152.8, 152.3, 144.2, 143.7, 139.9, 139.5, 139.2, 139.1, 138.9, 138.5, 138.2, 137.6, 136.7, 135.1, 135.0, 132.9, 132.8, 129.8, 129.5, 129.4, 129.1, 128.9, 128.8, 128.4, 128.3, 128.2, 128.1, 128.1, 128.0, 127.8, 127.7, 127.5, 127.4, 127.2, 127.1, 126.9, 126.7, 126.7, 126.6, 126.5, 126.4, 125.1, 124.5, 124.4, 124.1, 123.8, 117.5, 116.1, 115.0, 114.7, 73.4, 51.2, 42.6, 29.7, 27.8, 20.4, 20.4, 16.7, 16.5.

[0111] Chiral High Performance Liquid Chromatography: Chiral AZ column, V正己烷 / V 异丙醇 =90:10, flow rate 1.0mL / min, λ=254nm

[0112] tR(major)=9.70min, tR(minor)=12.34min.; tR(major)=7.18min, tR(minor)=17.69min.

[0113] High resolution: Calculated value: [M+Na] + :617.2298, measured value:617.2293.

[0114] Optical rotation: [α] D 25 =-131.57 (c = 1.00 in CHCl3).

[0115] Example 5

[0116] Preparation of Compound V-1

[0117]

[0118] Under argon atmosphere, 10 mol% Pd(PPh3)4, 10-membered ring compound 1 (0.05 mmol, 1.0 equiv.), Sub5 (0.1 mmol, 2.0 equiv.) and 2 mL of anhydrous dichloromethane were added to a dry Schlenk reaction tube. The reaction was carried out at 30°C for 30 minutes. Column chromatography (PE: EtOAc = 10: 1) was used to obtain 15-membered ring compound 5 (41.1 mg, isolated yield: 76%). 1 The dr value was determined by H NMR spectrum, and the enantiomeric excess (ee value) of the purified product was determined by chiral HPLC. The results showed 93% ee, >19:1 dr.

[0119] 1H NMR (400MHz, CDCl3) δ8.30 (d, J = 7.3Hz, 1H), 7.86-7.76 (m, 2H), 7.57-7.40 (m, 7H), 7.33-7.23 (m, 1H), 7.24(d,J=1.4Hz,1H),7.18(d,J=9.1Hz,1H),7.01(d,J=7.1Hz,1H),5.79-5.55(m,1H),5.63(s,1H),5. 62-5.55(m,1H),5.07(s,1H),4.99(s,1H),4.99-4.92(m,1H),4.57(d,J=11.4Hz,1H),4.34-4.30(m,2 H),2.63(d,J=13.9Hz,1H),2.49-2.44(m,1H),2.29(d,J=13.8Hz,1H),2.20-2.15(m,1H),1.78(s,3H).

[0120] 13 C NMR (100MHz, CDCl3) δ180.1,164.5,151.6,151.3,141.5,139.4,139.3,134.8,132.9,129.6,129.6,129.1,128.8,128.7,128.5,128.1, 128.1,127.4,127.4,126.4,126.4,125.0,124.3,123.8,123.4,123.4,121.3,117.1,112.8,106.1,71.9,62.9,54.6,40.6,34.9,20.0.

[0121] Chiral HPLC: Chiral IB N-5 column, V 正己烷 / V 异丙醇 =90:10, flow rate 1.0mL / min, λ=254nm

[0122] tR(major)=5.94min, tR(minor)=6.65min

[0123] High resolution: Calculated value: [M+Na] + :595.2455, measured value:595.2458.

[0124] Optical rotation: [α] D 25 =-27.23 (c = 1.00 in CHCl3).

[0125] Examples II-1 to II-9

[0126] The compounds listed in Table 2 were prepared according to the method of Example 2, except that substrate 1 was replaced by 1-X listed in Table 2.

[0127] Table 2

[0128]

[0129]

[0130]

[0131] The applications of biaryl axial chiral macrocycle II-1 in ion recognition are as follows:

[0132] The host chiral 20-membered ring II-1 is mixed with the guest (R)-prolinol and (S)-prolinol in equal moles, respectively, by 1 H NMR detection, such as Figure 1 As shown, it was found that the chemical shifts of the two were different by 0.1 ppm, indicating that the host chiral 20-membered ring II-1 has a certain molecular recognition effect on the guest prolinol.

[0133] The host chiral 20-membered ring II-1 is mixed with the guest (R,R)-cyclohexanediamine and (S,S)-cyclohexanediamine in equal moles, respectively, by 1 H NMR detection, such as Figure 2 As shown, it was found that the chemical shifts of the two were different by 0.105 ppm, indicating that the host chiral 20-membered ring II-1 had a certain molecular recognition effect on the guest cyclohexanediamine.

[0134] Examples III-1 to III-4

[0135] The compounds listed in Table 3 were prepared according to the method of Example 3, except that substrate 1 was replaced by 1-X listed in Table 2.

[0136] Table 3

[0137]

[0138] Examples IV-1 to IV-4

[0139] The compounds listed in Table 4 were prepared according to the method of Example 4, except that substrate 1 was replaced by 1-X listed in Table 2, and the enone intermediate was replaced by Int1-X in the table.

[0140] Table 4

[0141]

[0142] Examples V-1 to V-6

[0143] The compounds listed in Table 4 were prepared according to the method of Example 5, except that substrate 1 was replaced by 1-X listed in Table 2, and substrate Sub5 was replaced by Sub5-X in the table.

[0144] Table 4

[0145]

[0146]

[0147] It can be seen from the above that a series of biaryl axial chiral macrocyclic compounds can be prepared based on the method of the present invention, and the preparation steps of the method are simple, the conditions are mild, the yield is high and the enantiomeric selectivity is high.

[0148] The embodiments of the present invention have been described above, and the above description is exemplary, not exhaustive, and is not limited to the disclosed embodiments. Many modifications and changes will be apparent to those skilled in the art without departing from the scope and spirit of the described embodiments.

Claims

1. A biphenyl axial chiral meso-macrocyclic compound, characterized in that: The biphenyl axial chiral meso-macrocyclic compound is a meso-cyclic lactone compound, a macrocyclic compound synthesized by a dipolar cyclization reaction between meso-cyclic lactone compounds, or a macrocyclic compound synthesized by a dipolar cyclization reaction between a meso-cyclic lactone compound and a second reaction substrate; the second reaction substrate is selected from at least one of a benzofuranone-derived imine, a diazo compound enone intermediate, or a cyclopropane derived from γ-butyrolactone; Wherein, the mesocyclic lactone compound is as shown in formula (I): In formula (I), R 1 -R 3 are each independently hydrogen, C1-C5 alkyl or C6-C10 aryl, or R 1 , R 2 Form a C3-C8 ring or form a naphthyl group together with the phenyl group substituted by it; R 4 At least one selected from hydrogen, C1-C5 alkyl, C1-C5 alkoxy, halogen, C6-C10 aryl, C3-C10 alkynyl, C3-C6 ester and biboric acid ester.

2. The biphenyl axial chiral meso-macrocyclic compound according to claim 1, wherein R 1 -R 2 is hydrogen, R 3 is ethyl or phenyl; or, R 2 -R 3 is hydrogen, R 1 is methyl, ethyl, n-propyl or n-butyl; or, R 3 is hydrogen, R 1 , R 2 Form a C4 ring, a C5 ring, or form a naphthyl group together with the phenyl group substituted therewith; R 4 is hydrogen, 3-methoxy, 3-methyl, 3-ethyl, 3-benzyl, 3-bromo, 3-phenyl, 3-isopropenyl, 4-methyl, 4-phenyl, 4-bromo, 4-borate, 4-phenylethynyl or 4-ester.

3. The biphenyl axial chiral meso-macrocyclic compound according to claim 1, wherein The structural formulas of the benzofuranone-derived imine, the diazo compound enone intermediate and the γ-butyrolactone-derived cyclopropane are shown in Formula (1) to Formula (3), respectively: In formula (2), R 5 is a C6-C10 aryl group, a halogen-substituted C6-C10 aryl group or a naphthyl group, preferably a phenyl group, a 4-chlorophenyl group or a 2-naphthyl group; In formula (3), R 6 It is a C6-C10 aryl group, a halogen-substituted C6-C10 aryl group or a naphthyl group, and is preferably a phenyl group, a 4-chlorophenyl group, a 4-methylphenyl group or a 2-naphthyl group.

4. The biphenyl axial chiral meso-macrocyclic compound according to claim 3, wherein The macrocyclic compound is selected from at least one of the compounds represented by formula (II) to formula (V); R in formula (II) to formula (V) 1 -R 4 With R in formula (I) 1 -R 4 The definition is the same, R 5 With R in formula (2) 5 The definition is the same, R 6 With R in formula (3) 6 The definitions are the same; Preferably, in formula (II), R 2 -R 3 is hydrogen, R 1 is methyl or n-propyl; or, R 1 -R 2 is hydrogen, R 3 is phenyl; R 4 is hydrogen, 3-methyl, 3-benzyl, 3-bromo or 4-bromo; Preferably, in formula (III), R 2 -R 3 is hydrogen, R 1 is methyl; or, R 1 -R 2 is hydrogen, R 3 is phenyl; R 4 is hydrogen or 4-bromo; Preferably, in formula (IV), R 2 -R 3 is hydrogen, R 1 is methyl, R 4 is hydrogen; Preferably, in formula (V), R 2 -R 3 is hydrogen, R 1 is methyl, R 4 It is hydrogen or 3-bromo.

5. The biphenyl axial chiral meso-macrocyclic compound according to claim 1, wherein The diazo compound enone intermediate is an enone produced by Wollf rearrangement of the diazo compound under light conditions; the diazo compound is as shown in formula (4); R in formula (4) 5 With R in formula (2) 5 The definition is the same.

6. The biphenyl axial chiral medium macrocyclic compound according to claim 5, wherein The diazo compound ketene intermediate is prepared by a preparation method comprising the following steps: Under the protection of a first inert gas and in the presence of a first solvent, the diazo compound is subjected to light treatment to obtain the diazo compound enone intermediate; Preferably, the first inert gas is argon and / or nitrogen; the first solvent is dichloromethane; the light treatment uses visible light, the wavelength of the visible light is 350-400nm, the light intensity is 8-15W, the light temperature is 0-40°C, and the light time is 2-6h.

7. The method for synthesizing the biphenyl axial chiral meso-macrocyclic compound according to any one of claims 1 to 6, characterized in that: The steps include: Step (a): Under the protection of a second inert gas, dissolving the six-membered biaryl lactone compound represented by formula (5), the tert-butyl carbonate compound represented by formula (6), the first catalyst and the first chiral ligand in a second solvent, and performing an asymmetric cyclization reaction to obtain the medium-ring lactone compound; R in formula (5) 1 -R 4 With R in formula (I) 1 -R 4 The definitions are the same; and optionally step (b); Step (b): allowing the mesocyclic lactone compounds to undergo a dipolar cyclization reaction, or allowing the mesocyclic lactone compound to undergo a dipolar cyclization reaction with a second reaction substrate to obtain a biphenyl axial chiral macrocyclic compound.

8. The synthesis method according to claim 7, wherein The first catalyst is tris(dibenzylideneacetone)dipalladium chloroform adduct and / or tris(dibenzylideneacetone)dipalladium; The first chiral ligand is a compound having a structure represented by formula (7) or a compound having a structure represented by formula (8); The second solvent is toluene and / or o-xylene; The second inert gas is argon and / or nitrogen; The molar ratio of the hexaaryl lactone compound, the tert-butyl carbonate compound, the chiral ligand and the first catalyst is 1:1.5-2.0:0.12-0.15:0.05 - 0.06; The temperature of the asymmetric cyclization reaction is 10-20°C.

9. The synthesis method according to claim 7, wherein In step (b), the dipolar cyclization reaction between the mesocyclic lactone compounds comprises: Under the protection of a third inert gas, one or two mesocyclic lactone compounds, a second catalyst and a second chiral ligand are dissolved in a third solvent to carry out a dipolar cyclization reaction to obtain the biphenyl axial chiral macrocyclic compound; Preferably, the second catalyst is tris(dibenzylideneacetone)dipalladium chloroform adduct and / or tris(dibenzylideneacetone)dipalladium; the second chiral ligand is a compound having a structure shown in formula (7) or a compound having a structure shown in formula (8); Preferably, the third inert gas is argon and / or nitrogen; the third solvent is 1,4-dioxane and / or tetrahydrofuran; the molar ratio of the total amount of the mesocyclic lactone compound, the second chiral ligand and the second catalyst is 1:0.12-0.15:0.05-0.06; Preferably, the conditions of the dipolar cyclization reaction include: temperature of 0 to 40° C. and time of 2 to 10 h.

10. The synthesis method according to claim 7, wherein In step (b), the dipolar cyclization reaction between the mesocyclic lactone compound and the second reaction substrate comprises: Under the protection of a fourth inert gas, dissolving the mesocyclic lactone compound, the second reaction substrate and the third catalyst in a fourth solvent to undergo a dipolar cyclization reaction to obtain the biphenyl axial chiral macrocyclic compound; Preferably, the fourth inert gas is argon and / or nitrogen; the third catalyst is Pd(PPh3)4 and / or tris(dibenzylideneacetone)dipalladium; the fourth solvent is dichloromethane and / or 1,2-dichloroethane; the molar ratio of the medium-ring lactone compound, the second reaction substrate and the third catalyst is 1:3-4:0.1-0.12; Preferably, the conditions of the dipolar cyclization reaction include: temperature of 0 to 40° C. and time of 2 to 10 h.

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