Method for constructing surface chiral [2, 2] paracyclophane compound through activation of asymmetric carbon-hydrogen bonds under catalysis of cobalt

Abstract

The invention provides a method for constructing a planar chiral [2, 2] paracyclophane compound by activating asymmetric carbon-hydrogen bonds under the catalysis of cobalt, which comprises the following steps: under the action of a cobalt catalyst and a chiral assistant, carrying out asymmetric C-H activation reaction on aryl hydrazone and racemic 4-ethynyl-[2, 2] paracyclophane, and carrying out kinetic resolution on the racemic 4-ethynyl-[2, 2] paracyclophane to obtain the planar chiral [2, 2] paracyclophane compound. After the reaction is finished, separation is carried out to obtain planar chiral 4-ethynyl-[2, 2] paracyclophane and a planar chiral 4-isoquinoline-[2, 2] paracyclophane compound; the invention further develops a research technology for catalyzing C-H activation by a cheap transition metal, and expands a synthetic strategy of the planar chiral [2, 2] paracyclophane compound; the reaction substrate is wide in adaptability, and the product is high in stereoselectivity; the multi-planar chiral [2, 2] paracyclophane compound is synthesized, the synthesis method is simple and convenient, the atom economy is good, and the synthesis efficiency is high.

Description

Technical Field

[0001] This invention relates to the field of compound synthesis technology, and in particular to a method for constructing chiral [2,2] cyclopeptides using cobalt-catalyzed asymmetric carbon-hydrogen bond activation. Background Technology

[0002] [2.2] Para-cyclophanes consist of two coplanar stacked benzene rings that interact and connect at the para-bridgehead carbon atom via ethylene bridges. [2.2] Para-cyclophanes are interesting molecules with unique photophysical and photoelectric properties, and have wide applications in materials science, medicinal chemistry, and as development of chiral ligands or organic catalysts, such as surface-mounted MOF structures, the dopamine D3 receptor antagonist FAUC 418, and the chiral phosphine ligand phanephos. Therefore, the synthesis of such facet-chiral [2,2] para-cyclophane compounds has significant practical implications and application prospects.

[0003] Despite their significant importance, the synthesis of optically pure planar chiral [2.2] cyclophanes remains a considerable challenge in organic synthesis, with current methods primarily relying on chiral high-performance liquid chromatography (HPLC) to separate racemic functionalized [2.2] cyclophanes or chemical resolution using stoichiometric chiral reagents. Although recent advances in catalytic kinetic resolution and asymmetric catalysis have improved the feasibility of synthesizing chiral [2.2] cyclophanes, the structural diversity of the resulting frameworks remains limited. Summary of the Invention

[0004] To address the shortcomings of existing technologies, this invention provides a method for constructing faceted chiral [2,2]-p-cyclophanes using cobalt-catalyzed asymmetric C-H bond activation. This invention utilizes inexpensive and readily available cobalt salts as catalysts, easily synthesized salicyloxazoline as a chiral auxiliary, and easily synthesized arylhydrazones and racemic 4-ethynyl-[2,2]-p-cyclophanes as substrates. This method efficiently synthesizes faceted chiral [2,2]-p-cyclophanes and resolves the highly enantioselective 4-ethynyl-[2,2]-p-cyclophane starting material.

[0005] The technical solution of this invention is: a method for constructing chiral [2,2]-paired cycloadenosine compounds by cobalt-catalyzed asymmetric carbon-hydrogen bond activation, wherein the method is as follows:

[0006] In the presence of a cobalt catalyst, a chiral auxiliary agent, and a solvent, arylhydrazones and racemic 4-ethynyl-[2,2]-p-cyclophanes undergo an asymmetric CH activation reaction, followed by kinetic resolution of the racemic 4-ethynyl-[2,2]-p-cyclophanes. After the reaction, chiral 4-ethynyl-[2,2]-p-cyclophanes and chiral 4-isoquinoline-[2,2]-p-cyclophanes are obtained by separation. The synthesis is as follows:

[0007]

[0008] In the formula, R represents H, para- and meta-alkyl, para- and meta-halogen, phenyl, alkoxy, phenoxy, methylthio, cyano, ester, trifluoromethyl, trifluoromethoxy, amide, or morpholino; 1 The aryl group is alkyl, substituted, or unsubstituted, wherein the substituent on the aryl group is a halogen or alkyl group; R 2 The substituted group is H, or a bromine substituent at positions 7, 15, and 16. Preferably, R is H, a para- or meta-C1–C4 alkyl group, a para- or meta-halogen, a phenyl group, a C1–C4 alkoxy group, a phenoxy group, a methylthio group, a cyano group, a C1–C4 alkoxycarbonyl group, a trifluoromethyl group, a trifluoromethoxy group, a C1–C4 amide group, or a morpholino group; 1 The phenyl group is a C1-C4 alkyl group, substituted or unsubstituted, wherein the substituent on the phenyl group is F, Cl, Br or a C1-C4 alkyl group; R 2 It is a bromine substituent at positions H, 7, 15, and 16.

[0009] During the reaction, by controlling the reaction with chiral auxiliaries, the asymmetric CH activation reaction products can be made to have an ee value of 86%–96%, and the starting material with an ee value of 40%–99% can be separated.

[0010] Preferably, the molar ratio of the arylhydrazone substrate, the racemic 4-ethynyl-[2,2]-cyclophane, the cobalt catalyst, and the chiral auxiliaries is 1.5–2.0:1:0.08–0.1:0.1–0.2, and more preferably 1.5:1:0.08:0.1.

[0011] Preferably, the arylhydrazone and the racemic 4-ethynyl-[2,2]-p-cycloaven undergo an asymmetric CH activation reaction, and the racemic 4-ethynyl-[2,2]-p-cycloaven is kinetically resolved. After the reaction is completed, the chiral 4-ethynyl-[2,2]-p-cycloaven and the chiral 4-isoquinoline-[2,2]-p-cycloaven compounds are obtained by separation.

[0012] Preferably, the cobalt catalyst is cobalt acetate tetrahydrate.

[0013] Preferably, the chiral auxiliary is a chiral salicyloxazoline, 2-((R)-4-((S)-1-(tert-butoxy)ethyl)-4,5-dihydrooxazol-2-yl)-6-(tert-butyldimethylsilyl)phenol.

[0014] Preferably, the solvent is a mixture of ethanol and acetonitrile, and the amount of solvent is: 0.8 mL of ethanol and 0.2 mL of acetonitrile per 0.15 mmol of arylhydrazone substrate.

[0015] Preferably, the activation reaction temperature is 40-50°C, more preferably 45°C, and the reaction time is 84-120 hours.

[0016] Preferably, the separation process is as follows:

[0017] After the reaction was complete, the reactants were diluted with dichloromethane, filtered through a diatomaceous earth filter, and washed with dichloromethane. The solvent was then removed directly under vacuum, and the product was obtained by chromatography.

[0018] The beneficial effects of this invention are as follows:

[0019] 1. This invention uses arylhydrazone and racemic 4-ethynyl-[2,2]-p-cyclophanes as raw materials, transition metal Co as a catalyst, and chiral salicyloxazoline as a chiral auxiliary to kinetically resolve racemic 4-ethynyl-[2,2]-p-cyclophanes through asymmetric CH activation, thereby synthesizing a variety of faceted chiral [2,2]-p-cyclophanes.

[0020] 2. This invention realizes the synthesis of chiral [2,2] cycloadenosine compounds by transition metal catalytic asymmetric CH activation, further developing the research technology of transition metal catalytic CH activation, and expanding the synthesis strategy of chiral cycloadenosine compounds;

[0021] 3. The present invention has broad substrate adaptability and strong product stereoselectivity. By controlling the chirality of chiral salicyloxazoline, the product can have a very high ee value.

[0022] 4. This invention synthesizes a variety of facet-chiral [2,2] cyclopeptides. The synthesis method is simple, has good atom economy, and high synthesis efficiency. Attached Figure Description

[0023] Figure 1 The HPLC chromatograms of compound 3aa and its racemic mixture obtained in Example 3aa are shown. The HPLC conditions were as follows: OD-H column, mobile phase: n-hexane / isopropanol = 90 / 10, flow rate = 1.0 mL / min, λ = 254 nm.

[0024] Figure 2 The HPLC chromatograms of the chiral raw material (Sp)-2a and its racemic mixture obtained by resolution in Example 3aa are shown. The HPLC conditions were as follows: OD-H column, mobile phase: n-hexane / isopropanol = 90 / 10, flow rate = 1.0 mL / min, λ = 254 nm.

[0025] Figure 3Optical and chiral optical properties of compound 3aa and its enantiomer-derived compound 4e: a. UV-Vis absorption spectrum and fluorescence spectrum; b. asymmetry factor curve of circularly polarized emission; c. circular dichroism spectrum; d. circularly polarized emission spectrum. Detailed Implementation

[0026] The specific embodiments of the present invention will be further described below with reference to the accompanying drawings:

[0027] Example 3aa

[0028] In a reactor, 0.15 mmol of arylhydrazone substrate, 0.1 mmol of racemic 4-ethynyl-[2,2]-p-cyclophane, 0.008 mmol of cobalt acetate tetrahydrate, 0.01 mmol of chiral auxiliary 2-((R)-4-((S)-1-(tert-butoxy)ethyl)-4,5-dihydrooxazol-2-yl)-6-(tert-butyldimethylsilyl)phenol, a magnetic stir bar, 0.8 mL of ethanol, and 0.2 mL of acetonitrile were added. The reactor was placed on an aluminum heating module and heated at 45 °C for 84 hours. After the reaction, the reactants were diluted with dichloromethane, filtered through a diatomaceous earth filter, and washed with dichloromethane. The solvent was removed directly under vacuum, and the product 3aa was obtained by chromatography with a yield of 50% and an ee value of 92%, as well as the chiral starting material (Sp)-2a with a yield of 47% and an ee value of 99%. The HPLC chromatograms of compound 3aa and its racemic mixture are shown below. Figure 1 HPLC chromatograms of the chiral starting material (Sp)-2a and its racemic mixture are shown below. Figure 2 .

[0029] The structure of product 3aa is as follows:

[0030]

[0031] 1 H NMR (400MHz, Chloroform-d) δ8.18(d,J=8.3Hz,1H),7.95(d,J=8.3Hz,1H),7.74(d,J=6.8Hz,2H),7.62(t,J=7.5Hz,1H),6.89(d, J=2.2Hz,1H),6.70–6.54(m,6H),3.90–3.80(m,1H),3.29–3.12(m,2H),3.15–3.05(m,5H),3.08–2.88(m,2H),2.73–2.59(m,1H). 13CNMR(101MHz,Chloroform-d)δ158.2,152.3,140.7,140.1,139.6,139.4,138.6,136.8,136.4,133.1,133.0,132.9 ,132.7,132.3,130.2,130.0,127.7,126.9,126.1,125.7,118.5,35.6,35.4,35.0,34.8,22.7.HRMS(ESI)m / z[M+H] + For C 26 H 24 The calculated value of N is 350.1903, and the measured value is 350.1906.

[0032] The determination of the ee value of compound 3aa was performed by HPLC (Daicel Chiralcel OD-H column), mobile phase: n-hexane / isopropanol = 90 / 10, flow rate = 1.0 mL / min, λ = 254 nm, t(peak 1) = 7.395 min, t(peak 2) = 8.475 min: 92% ee.

[0033] The structure of product (Sp)-2a is as follows:

[0034]

[0035] 1 H NMR(400MHz,Chloroform-d)δ7.02(dd,J=7.9,1.9Hz,1H),6.58(s,1H),6.58–6.44(m,5H),3.61(ddd,J=13.1,10.4,2.8Hz,1H) ,3.30(s,1H),3.25(ddd,J=12.8,10.3,5.1Hz,1H),3.18–3.03(m,4H),3.03–2.93(m,1H),2.88(ddd,J=13.0,10.6,5.2Hz,1H). 13 CNMR(101MHz,Chloroform-d)δ143.2,139.9,139.7,139.5,137.8,134.0,133.5,133 .4,132.9,132.7,130.1,123.9,84.1,80.4,35.6,35.3,34.4,34.3.HRMS(EI)m / z[M] + For C 18 H 16 Calculated value: 232.1247; Measured value: 232.1250.

[0036] The determination of the ee value of compound (Sp)-2a was performed by HPLC (Daicel Chiralcel OD-H column), with mobile phase: n-hexane / isopropanol = 90 / 10, flow rate = 1.0 mL / min, λ = 254 nm, t(peak 1) = 6.317 min, t(peak 2) = 7.155 min: 99% ee.

[0037] Examples 3aa~3aaa, 3ab, 3ac

[0038] The operation steps are the same as in Example 3aa, except that by changing the substituents on the raw materials, products with different facet chiral [2,2] pairs of cycloadenosines can be obtained, as shown below:

[0039]

[0040] Application Example 1

[0041] Compound 3aa and its enantiomers were converted to compound 4e and subjected to optical measurements, yielding UV-Vis absorption, fluorescence, circular dichroism, luminescence asymmetry factor, and circularly polarized emission spectra. In the UV-Vis absorption and fluorescence measurements, compound 4e had a value of 10. -5 M in DCM solution. In the measurements of circular dichroism spectroscopy, luminescence asymmetry factor, and circularly polarized emission spectroscopy, compound 4e has a value of 10. -4 M's DCM solution. Results as follows: Figure 3 As shown, the results indicate that the derivatives of the chiral cyclopeptide compounds of the present invention possess excellent fluorescence and circularly polarized luminescence properties.

[0042] The conversion of compound 3aa to compound 4e occurs as follows:

[0043]

[0044] The embodiments and descriptions above are merely illustrative of the principles and preferred embodiments of the present invention. Various changes and modifications may be made to the present invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the present invention as claimed.

Claims

1. A method for constructing faceted chiral [2,2]-paired cycloadenosine compounds by cobalt-catalyzed asymmetric C-H bond activation, characterized in that, include: In the presence of a cobalt catalyst, a chiral auxiliary agent, and a solvent, arylhydrazones and racemic 4-ethynyl-[2,2]-p-cyclophanes undergo an asymmetric CH activation reaction, followed by kinetic resolution of the racemic 4-ethynyl-[2,2]-p-cyclophanes. After the reaction, chiral 4-ethynyl-[2,2]-p-cyclophanes and chiral 4-isoquinoline-[2,2]-p-cyclophanes are obtained by separation. The synthesis is as follows: In the formula, R represents H, para- and meta-alkyl, para- and meta-halogen, phenyl, alkoxy, phenoxy, methylthio, cyano, ester, trifluoromethyl, trifluoromethoxy, amide, or morpholino; 1 The aryl group is alkyl, substituted, or unsubstituted, wherein the substituent on the aryl group is a halogen or alkyl group; R 2 It is a bromine substituent at positions H, 7, 15, and 16.

2. The method for constructing faceted chiral [2,2]-paired cycloadenosine compounds by cobalt-catalyzed asymmetric C-H bond activation according to claim 1, characterized in that: R is H, para- and meta-C1–C4 alkyl, para- and meta-halogen, phenyl, C1–C4 alkoxy, phenoxy, methylthio, cyano, C1–C4 alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, C1–C4 amide, or morpholino; 1 The phenyl group is a C1-C4 alkyl group, substituted or unsubstituted, wherein the substituent on the phenyl group is F, Cl, Br or a C1-C4 alkyl group; R 2 It is a bromine substituent at positions H, 7, 15, and 16.

3. The method for constructing chiral [2,2]-paired cycloadenosine compounds by cobalt-catalyzed asymmetric C-H bond activation according to claim 1, characterized in that: The molar ratio of arylhydrazone, racemic 4-ethynyl-[2,2]-cyclophane, cobalt catalyst, and chiral auxiliaries is 1.5–2.0:1:0.08–0.1:0.1–0.

2.

4. The method for constructing faceted chiral [2,2]-paired cycloadenosine compounds by cobalt-catalyzed asymmetric C-H bond activation according to claim 1, characterized in that: The cobalt catalyst is cobalt acetate tetrahydrate.

5. The method for constructing chiral [2,2]-paired cycloadenosine compounds by cobalt-catalyzed asymmetric C-H bond activation according to claim 1, characterized in that: The chiral adjuvant is a chiral salicyloxazoline with the following structural formula:

6. The method for constructing faceted chiral [2,2]-paired cycloadenosine compounds by cobalt-catalyzed asymmetric C-H bond activation according to claim 1, characterized in that: The solvent is a mixture of ethanol and acetonitrile, and the amount of solvent is: 0.8-2.0 mL of ethanol and 0.2-0.5 mL of acetonitrile per 0.15 mmol of arylhydrazone substrate.

7. The method for constructing faceted chiral [2,2]-paired cycloadenosine compounds by cobalt-catalyzed asymmetric C-H bond activation according to claim 1, characterized in that: The activation reaction is carried out at a temperature of 40–50°C for 84–120 hours.

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