CN112479851B - Zanthoxylum bungeanum ketene derivative, preparation method and application thereof - Google Patents

Zanthoxylum bungeanum ketene derivative, preparation method and application thereof Download PDF

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CN112479851B
CN112479851B CN202011282034.6A CN202011282034A CN112479851B CN 112479851 B CN112479851 B CN 112479851B CN 202011282034 A CN202011282034 A CN 202011282034A CN 112479851 B CN112479851 B CN 112479851B
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sanshool
zey
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许旭东
孙忠浩
马国需
曹丽
田瑜
陈德力
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Institute of Medicinal Plant Development of CAMS and PUMC
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Abstract

The invention provides a zanthoxylum fruit ketene derivative, and a preparation method and application thereof. The zanthoxylum ketone derivative comprises a first derivative of zanthoxylum ketone (-) -zeanone configuration and a second derivative of zanthoxylum ketone with (+) -zeanone configuration; the first derivative has a structure of formula (II), formula (III) or formula (IV); the second derivative has a structure of formula (V), formula (VI), formula (VII), formula (VIII), formula (IX) or formula (X). The zanthoxylum ketone derivative with the specific structure has better anti-tumor activity, has great influence on the IC50 value of malignant melanoma, human liver cancer, human neuroblastoma and canine breast tumor, and can enable the IC50 value to be a very small value. Can be used for preparing medicine for resisting malignant melanoma, human liver cancer, human neuroblastoma and canine breast tumor.

Description

Zanthoxylum piperitum ketene derivative, and preparation method and application thereof
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to a zanthoxylum fruit ketene derivative, and a preparation method and application thereof.
Background
Zanthoxylum piperitum ketene is a cyclohexenone compound. Zanthoxylum ketene extracted from Zanthoxylum bungeanum (Uvaria grandiflora Roxb.) of Gynura of family Lycopersiaceae has (-) -zeanone configuration, CAS number of 193410-84-3, and molecular formula of C 21 H 18 O 7 Structural formula is
Figure BDA0002781107230000011
Pharmacological activity research shows that the (-) -zeylenone has better cytotoxic activity on various tumor cells and has the potential of being used as a lead compound to develop new drugs. However, the source problem of the xanthones is not solved at present, and the large demand of in vivo experiments on the compounds cannot be met.
Disclosure of Invention
In view of the above, the present invention aims to provide an application of a sanshool ketene derivative, and a preparation method and an application thereof.
In view of the above purposes, the invention provides a zanthoxylum ketone derivative, which comprises a first derivative of zanthoxylum ketone (-) -zearylone configuration and a second derivative of zanthoxylum ketone in (+) -zearylone configuration; the first derivative has a structure of formula (II), formula (III) or formula (IV); the second derivative has a structure of formula (V), formula (VI), formula (VII), formula (VIII), formula (IX) or formula (X);
Figure BDA0002781107230000012
wherein, in the formula (VIII), R is one of the following structures:
Figure BDA0002781107230000021
in formula (IX), R is one of the following structures:
H
Figure BDA0002781107230000022
in the formula (X), R 1 Is one of the following structures:
H
Figure BDA0002781107230000023
R 2 is one of the following structures:
Figure BDA0002781107230000024
the invention also provides a preparation method of the zanthoxylum bungeanum ketene derivative, which comprises the following steps:
reflux reaction of the zanthoxylum ketone (-) -zeylenone configuration and ammonia water to obtain a compound with a structure of a formula (II); or carrying out cis-dihydroxy acetone acetal protection reaction on the obtained compound with the structure shown in the formula (II) and p-toluenesulfonic acid monohydrate and 2, 2-dimethoxypropane to obtain a compound with the structure shown in the formula (III);
or
Carrying out asymmetric dihydroxylation reaction on the first reactant and hydrogenated quinine 1,4- (2, 3-naphthyridine) diether in a mixed solvent of tetrahydrofuran and water to obtain a second reactant; carrying out cis-dihydroxy protection reaction on the second reactant, triphosgene and pyridine to obtain a third reactant; carrying out elimination reaction of a carbonate ring on the third reactant in a mixed solvent of tetrahydrofuran and water; catalyzing the benzene reflux reaction to obtain a compound with a structure shown in a formula (V);
or
Protecting the compound with the structure of the formula (V) by cis-dihydroxy acetone acetal and subsequent protection to respectively obtain one of a compound with the structure of a formula (IV), a compound with the structure of a formula (IX), a compound with the structure of a formula (VIII) and a compound with the structure of a formula (X);
or
Reacting the second reactant with acetyl chloride under the catalysis of triethylamine and DMAP; reacting the obtained product with dichloromethane; reacting the obtained product with N, N-diisopropylethylamine and methylsulfonyl chloride to obtain compounds with structures of formula (VI) and formula (VII);
wherein the first reactant is of formula (XI); the second reactant is a structure of formula (XII); the third reactant is of a structure of formula (XIII);
Figure BDA0002781107230000031
the invention also provides an application of the zanthoxylum bungeanum ketene derivative or the zanthoxylum bungeanum ketene derivative prepared by the preparation method in preparing an anti-tumor medicament, wherein the tumor is at least one selected from malignant melanoma, human liver cancer, human neuroblastoma and canine breast tumor.
In one embodiment, the tumor is human neuroblastoma SH-SY5Y.
The embodiment of the invention also provides an anti-tumor drug which comprises the zanthoxylum piperitum ketene derivative or the zanthoxylum piperitum ketene derivative prepared by the preparation method of the zanthoxylum piperitum ketene derivative, and a medically acceptable auxiliary material, wherein the anti-tumor drug is selected from at least one of a drug for resisting malignant melanoma, a drug for resisting human liver cancer, a drug for resisting human neuroblastoma and a drug for resisting canine breast tumor.
In one embodiment, the anti-tumor drug is anti-human neuroblastoma SH-SY5Y drug.
From the above, the zanthoxylum fruit ketene derivative provided by the invention has the structure of formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX) or formula (X), and the preparation method and application thereof. The zanthoxylum ketone derivative with the specific structure has better anti-tumor activity, has great influence on the IC50 value of malignant melanoma, human liver cancer, human neuroblastoma and canine breast tumor, and can enable the IC50 value to be a very small value. Therefore, the zanthoxylum bungeanum ketene derivative provided by the invention can be applied to preparation of medicines for resisting malignant melanoma, medicines for resisting human liver cancer, medicines for resisting human neuroblastoma and medicines for resisting canine breast tumors.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the following detailed description is given with reference to specific embodiments.
The invention provides an application of a sanshool ketene derivative in preparing an anti-tumor medicament. The zanthoxylum ketone derivative comprises a first derivative of zanthoxylum ketone (-) -zeylenone configuration and a second derivative of zanthoxylum ketone (+) -zeylenone configuration. The first derivative has a structure of formula (II), formula (III) or formula (IV). The second derivative has a structure of formula (V), formula (VI), formula (VII), formula (VIII), formula (IX) or formula (X).
Figure BDA0002781107230000032
Figure BDA0002781107230000041
Wherein, in the formula (VIII), R is one of the following structures:
Figure BDA0002781107230000042
in formula (IX), R is one of the following structures:
H
Figure BDA0002781107230000043
in the formula (X), R 1 Is one of the following structures:
H
Figure BDA0002781107230000044
R 2 is one of the following structures:
Figure BDA0002781107230000045
the pimento ketene derivative with the structure of formula (VIII) provided by the invention preferably has any one of the following structures:
Figure BDA0002781107230000046
Figure BDA0002781107230000051
the zanthoxylum ketone derivative with the structure of formula (IX) provided by the invention preferably has any one of the following structures:
Figure BDA0002781107230000052
the zanthoxylum ketone derivative with the structure of formula (X) provided by the invention preferably has any one of the following structures:
Figure BDA0002781107230000053
the invention also provides a preparation method of the capsicum ketene derivative in the application, which comprises the following steps:
carrying out asymmetric dihydroxylation reaction on the first reactant and an asymmetric dihydroxylation reagent to obtain a second reactant; carrying out cis-dihydroxy protection reaction on the second reactant and triphosgene to obtain a third reactant; carrying out elimination reaction and benzene reflux reaction on the third reactant in sequence to obtain a compound with a structure shown in a formula (V); the first reactant is of formula (XI); the second reactant is of a structure shown in a formula (XII); the third reactant is of a structure of formula (XIII);
or
Carrying out cis-dihydroxy acetone acetal protection on the compound with the structure shown in the formula (V) with p-toluenesulfonic acid monohydrate and 2, 2-dimethoxypropane; reacting the compound obtained by the reaction with benzoyl chloride under the catalysis of triethylamine and DMAP to obtain a compound with a structure shown in a formula (IV);
Figure BDA0002781107230000061
or
Reflux reaction of the sanshool ketene (-) -zeylenone configuration and ammonia water to obtain a compound with a structure in a formula (II);
or
Carrying out cis-dihydroxy acetone acetal protection reaction on the compound with the structure shown in the formula (II) and p-toluenesulfonic acid monohydrate and 2, 2-dimethoxypropane to obtain a compound with the structure shown in the formula (III);
or
Reacting the second reactant with acetyl chloride under the catalysis of triethylamine and DMAP; reacting the obtained product with dichloromethane; reacting the obtained product with N, N-diisopropylethylamine and methylsulfonyl chloride to obtain compounds with structures of formulas (VI) and (VII);
or
Carrying out cis-dihydroxy acetone acetal protection on the compound with the structure shown in the formula (V), p-toluenesulfonic acid monohydrate and 2, 2-dimethoxypropane to obtain a compound with the structure shown in the formula (IX-7); reacting the compound with the structure of formula (IX-7), dicyclohexylcarbodiimide and substituted benzene compounds under the catalysis of DMAP to obtain one of the compounds with the structures of formulas (IX-1) to (IX-6);
or
Hydrolyzing one of the compounds with the structures of the formulas (IX-1) to (IX-6) with diluted hydrochloric acid to obtain a compound with a structure of a formula (VIII);
or
Reacting the compound with the structure of the formula (I) with an acyl chloride compound under the catalysis of triethylamine and DMAP to obtain the compound with the structure of the formula (X).
The preparation method of the compounds with the structures of the formulas (IX-1) to (IX-6) provided by the invention specifically comprises the following steps:
reacting the compound with the structure of the formula (IX-7) with dicyclohexylcarbodiimide and substituted benzene compounds under the catalysis of DMAP to obtain other compounds with the structure of the formula (IX); wherein the substituted benzene compound is selected from one of benzoyl chloride, p-fluorobenzoic acid, p-methoxybenzoic acid, p-methylbenzoic acid, cyclohexyl formic acid, phenylpropionic acid and phenylacetic acid.
The preparation method of the compound with the structure of the formula (X) provided by the invention specifically comprises the following steps:
reacting a compound with a structure shown in a formula (I) with an acyl chloride compound under the catalysis of triethylamine and DMAP to obtain a compound with a structure shown in a formula (X), namely one of compounds Zey-C1, QA2-19 (Zey-C2), zey-C3, zey-C4, zey-C5, zey-C6, zey-C7 and Zey-C8; wherein the acyl chloride compound is one selected from acetyl chloride, propionyl chloride, benzoyl chloride and cinnamoyl chloride.
Preferably, the molar ratio of the acyl chloride compound to the sanshool (+) -zeylenone configuration is 2. When the acyl chloride compound is acetyl chloride, a compound (compound Zey-C1) with a structure of formula (X-1) and a compound (compound Zey-C2) with a structure of formula (X-2) are obtained. When the acyl chloride compound is propionyl chloride, a compound (compound Zey-C3) with a structure of formula (X-3) and a compound (compound Zey-C4) with a structure of formula (X-4) are obtained. When the acyl chloride compound is benzoyl chloride, a compound (compound Zey-C5) with a structure of formula (X-5) and a compound (compound Zey-C6) with a structure of formula (X-6) are obtained. When the acyl chloride compound is cinnamoyl chloride, a compound (compound Zey-C7) with a structure of formula (X-7) and a compound (compound Zey-C8) with a structure of formula (X-8) are obtained.
The preparation method of the compound with the structure of formula (V) provided by the invention specifically comprises the following steps:
carrying out asymmetric dihydroxylation reaction on the first reactant and hydrogenated quinine 1,4- (2, 3-naphthyridine) diether in a mixed solvent of tetrahydrofuran and water to obtain a second reactant; carrying out cis-dihydroxy protection reaction on the second reactant, triphosgene and pyridine to obtain a third reactant; carrying out elimination reaction of carbonate ring on the third reactant in a mixed solvent of tetrahydrofuran and water; catalyzing the benzene reflux reaction to obtain the compound with the structure of the formula (V).
Wherein the step of obtaining the second reactant (compound QA 2-7) specifically comprises:
asymmetric dihydroxy groups were introduced into the first reactant (compound QA 2-6) by Sharpless Asymmetric Dihydroxylation (AD), yielding 2 chiral centers in one step, yielding a second reactant with an absolute configuration (compound QA 2-7).
The asymmetrical dihydroxylation agent is preferably AD-mix-alpha, the main component of which is (DHQ) 2 -PHAL (hydroquinine 1,4- (2, 3-naphthyridine) diether). Wherein (DHQ) 2PHAL has CAS number of 140924-50-1 and molecular formula of C 48 H 54 N 6 O 4 Structural formula is
Figure BDA0002781107230000071
The reaction condition is that the compounds QA2-6 and AD-mix-alpha react in the mixed solvent of tetrahydrofuran and water at normal temperature to carry out asymmetric dihydroxylation. The reagent can obtain the second reactant (the compound QA 2-7) with high yield, and the reaction chemical formula is shown as the formula c.
Figure BDA0002781107230000072
Wherein, the preparation of the first reactant (compound QA 2-6) specifically comprises the following steps: starting from commercial quinic acid, performing acetal and epoxidation to obtain an aldehyde ketone compound QA2-4; paraformaldehyde, 1M sodium bicarbonate and THF (tetrahydrofuran) are used as a solution for a compound QA2-4, DMAP (4-dimethylaminopyridine) is used as alkali, imidazole (imidazolyl) is used as an alkali catalyst to carry out Baylis-Hillmann (Bellis-Hillmann reaction), the yield can reach 85%, and a compound QA2-5 is obtained, wherein the reaction chemical equation is shown as a; acylating the compound by benzoyl chloride to obtain a compound QA2-6, wherein the reaction chemical equation is shown as a formula b.
Figure BDA0002781107230000081
Wherein the specific steps for obtaining the third reactant (compound QA 2-8) comprise: protecting cis-dihydroxy of a second reactant (compound QA 2-7) by using carbonate stable to acid, using triphosgene, taking pyridine as an acid-binding agent, and obtaining a third reactant (compound QA 2-8) under the protection of nitrogen, wherein the reaction chemical equation is shown as a formula d.
Figure BDA0002781107230000082
And (3) sequentially carrying out elimination reaction and benzene reflux reaction on the third reactant (compound QA 2-8) to obtain a compound (compound QA 2-12) with a structure of a formula (V), wherein the compound comprises the following components:
QA2-8 was dissolved in DCM (dichloromethane) (0.5 mmol/ml), and an equal volume of a mixed solution of TFA: H2O (6). The compound with the structure of the formula (V) is prepared by converting QA2-11 into QA2-12 by using DBU (1, 8-diazabicycloundecen-7-ene) as catalyst at benzene reflux. And the compound with the structure of the formula (V) has high yield which can reach 65 percent, and the reaction chemical equation is shown as a formula e.
Figure BDA0002781107230000083
The preparation method of the compound QA2-13 provided by the invention specifically comprises the following steps:
carrying out cis-dihydroxy acetone acetal protection on the compound (compound QA 2-12) with p-toluenesulfonic acid monohydrate and 2, 2-dimethoxypropane to obtain a compound (compound QA 2-13) with a structure shown in a formula (IX-7); the reaction chemical equation is shown as formula f.
Figure BDA0002781107230000091
The specific preparation method of the compounds with the structures of the formula (VI) and the formula (VII) provided by the invention comprises the following steps:
reacting a second reactant (compound QA 2-7) with acetyl chloride under the catalysis of triethylamine and DMAP (4-dimethylaminopyridine) to obtain a compound QA2-15; reacting with trichloroacetic acid to obtain a compound QA2-16; reacting with DIPEA (N, N-diisopropylethylamine) and methylsulfonyl chloride to obtain a compound (compound QA 2-17) with a structure shown in a formula (VI) and a compound (compound QA 2-18) with a structure shown in a formula (VII).
The specific preparation method of the compound (compound QA 1-8) with the structure of formula (IV) provided by the invention comprises the following steps:
carrying out cis-dihydroxy acetone acetal protection on the compound (compound QA 2-12) with p-toluenesulfonic acid monohydrate and 2, 2-dimethoxypropane to obtain a compound (compound QA 2-12) with a structure of formula (IX-7); reacting with benzoyl chloride under the catalysis of triethylamine and DMAP to obtain a compound (compound QA 1-8) with a structure of a formula (IV).
The specific preparation method of the compound (compound QA 1-6) with the structure of formula (II) provided by the invention comprises the following steps:
reflux reaction of the sanshool ketene (-) -zeylenone configuration and ammonia water to obtain a compound (compound QA 1-6) with a structure of a formula (II). Wherein, the raw material of the sanshool ketene (-) -zeylenone configuration is provided by the research institute of medicinal plants of Chinese academy of medical sciences.
The specific preparation method of the compound (compound QA 1-7) with the structure of the formula (III) provided by the invention comprises the following steps:
and (3) carrying out cis-dihydroxy acetone acetal protection reaction on the obtained compound with the structure of the formula (II) and p-toluenesulfonic acid monohydrate and 2, 2-dimethoxypropane to obtain a compound with the structure of the formula (III) (compound QA 1-7).
The preparation method of the zanthoxylum bungeanum ketene derivative with the structure of the formula (IX) provided by the invention specifically comprises the following steps:
carrying out cis-dihydroxy acetone acetal protection on the compound with the structure shown in the formula (V), p-toluenesulfonic acid monohydrate and 2, 2-dimethoxypropane to obtain a compound with the structure shown in the formula (IX-7) (compound QA 2-13); and reacting the compound with the structure of formula (IX-7), dicyclohexylcarbodiimide and substituted benzene compounds under the catalysis of DMAP to obtain one of the compounds with the structures of formulae (IX-1) to (IX-6).
The preparation method of the compounds with the structures of the formulas (IX-1) to (IX-6) specifically comprises the following steps:
reacting a compound (compound QA 2-13) with a structure shown in a formula (IX-7) with dicyclohexylcarbodiimide and substituted benzoic acid under the catalysis of DMAP to obtain one of compounds with structures shown in formulas (IX-1) to (IX-6), namely one of compounds Zey-B1, zey-B2, zey-B3, zey-B4, zey-B5 and Zey-B6. The mass ratio of the compound with the structure of the formula (IX-7) (compound QA 2-13) to DMAP, dicyclohexylcarbodiimide and substituted benzoic acid is 10.
Wherein the substituted benzoic acid is selected from one of p-fluorobenzoic acid, p-methoxybenzoic acid, p-methylbenzoic acid, cyclohexyl formic acid, phenylpropionic acid and phenylacetic acid.
Wherein, when the substituted benzene acid is selected from p-fluorobenzoic acid, the compound (compound Zey-B1) with the structure of formula (IX-1) is obtained. When the substituted benzoic acid is selected from p-methoxybenzoic acid, the compound (compound Zey-B2) with the structure of the formula (IX-2) is obtained. When the substituted benzoic acid is selected from p-methylbenzoic acid, the compound (compound Zey-B3) with the structure of formula (IX-3) is obtained. When the substituted benzene acid is selected from the group consisting of the cyclohexyl formic acid, the compound with the structure of the formula (IX-4) (compound Zey-B4) is obtained. When the substituted benzene acid is selected from phenylpropionic acid, the compound (compound Zey-B5) with the structure of formula (IX-5) is obtained. When the substituted benzoic acid is selected from phenylacetic acid, the compound with the structure of the formula (IX-6) (compound Zey-B6) is obtained.
The preparation method of the zanthoxylum bungeanum ketene derivative with the structure of the formula (VIII) provided by the invention specifically comprises the following steps:
and (3) hydrolyzing one of the compounds with the structures of the formulas (IX-1) to (IX-6) with diluted hydrochloric acid to obtain the compound with the structure of the formula (VIII), namely one of the compounds Zey-A1, zey-A2, zey-A3, zey-A4, zey-A5 and Zey-A6. The compound was dissolved in tetrahydrofuran and reacted at room temperature. The molar ratio of the compounds with the structures of the formulas (IX-1) to (IX-6) to the diluted hydrochloric acid is 0.65.
Wherein when the reactant is selected from the compound with the structure of the formula (IX-1), the compound with the structure of the formula (VIII-1) (compound Zey-A1) is obtained. When the substituted benzoic acid is selected from the formula (IX-2), a compound (compound Zey-A2) with the structure of the formula (VIII-2) is obtained. When the substituted benzoic acid is selected from the formula (IX-3), a compound (compound Zey-A3) with the structure of the formula (VIII-3) is obtained. When the substituted benzoic acid is selected from the formula (IX-4), a compound (compound Zey-A4) with the structure of the formula (VIII-4) is obtained. When the substituted benzoic acid is selected from the formula (IX-5), a compound (compound Zey-A5) with the structure of the formula (VIII-5) is obtained. When the substituted benzoic acid is selected from the formula (IX-6), a compound (compound Zey-A6) with the structure of the formula (VIII-6) is obtained.
The embodiment of the invention also provides an application of the zanthoxylum bungeanum ketene derivative or the zanthoxylum bungeanum ketene derivative prepared by the preparation method in preparing an anti-tumor medicament, wherein the tumor is at least one selected from malignant melanoma, human liver cancer, human neuroblastoma and canine breast tumor.
In one embodiment, the tumor is human neuroblastoma SH-SY5Y.
The embodiment of the invention also provides an anti-tumor drug which comprises the zanthoxylum piperitum ketene derivative or the zanthoxylum piperitum ketene derivative prepared by the preparation method of the zanthoxylum piperitum ketene derivative, and a medically acceptable auxiliary material, wherein the anti-tumor drug is selected from at least one of a drug for resisting malignant melanoma, a drug for resisting human liver cancer, a drug for resisting human neuroblastoma and a drug for resisting canine breast tumor.
In one embodiment, the anti-tumor drug is anti-human neuroblastoma SH-SY5Y drug.
Wherein, the name and the structure of the partial derivatives of sanshool (+) -zeylenone configuration are shown in the table 3.2.
TABLE 3.2 Compound names and structures
Figure BDA0002781107230000101
Figure BDA0002781107230000111
Figure BDA0002781107230000121
In order to further illustrate the present invention, the following detailed description is given with reference to examples.
EXAMPLE 1 Synthesis of Compound QA2-1
Quinic acid (5.5g, 23.6mmol) is dissolved in 100mL of anhydrous methanol, 2, 3-butanedione (4.53mL, 86mmol), trimethyl orthoformate (12.89mL, 118mmol) and (+/-) camphorsulfonic acid (4.53mL, 86mmol) are added with stirring, and the mixture is refluxed at 70 ℃ for 10 hours. And adding 5mL of triethylamine, quenching the reaction, and concentrating to obtain a crude product. Purification by silica gel column chromatography gave compound QA2-1 (6.69 g) as a white powder in 90% yield.
HRMS(ESI):m/z calcd.C 13 H 21 O 7 [M+H] + :289.1287,found 289.1297
EXAMPLE 2 Synthesis of Compound QA2-3
Compound QA2-1 (6.69g, 21.2mmol) is dissolved in 100mL of anhydrous methanol, sodium borohydride (1.9g, 50mmol) is added in portions with stirring, and the reaction is stirred vigorously at 0 ℃ for 2h. After TLC detection reaction, adding 5mL water to quench, adding 5mL diluted hydrochloric acid, standing, and concentrating to obtain crude product. Purification by silica gel column chromatography (dichloromethane-methanol, 10) gave crude compound QA2-2 (5.4 g) as a white powder in 87% yield, which was used in the next step without purification.
Phosphate buffer (0.2M, ph = 7) was added to a reaction flask containing crude QA2-2 (5.4g, 18.44mmol), and sodium periodate was added in portions under ice bath. The reaction is carried out at room temperature, TLC detection shows that the reaction is finished, 100mL of methylene chloride multiplied by 3 is added for extraction, and the crude product is obtained by concentration. The compound QA2-3 (3.8 g) was purified by means of a silica gel column chromatography to obtain a white powder with a yield of 80%.
HRMS(ESI):m/z calcd.C 12 H 20 NaO 6 [M+Na] + :283.1158,found 283.1173
EXAMPLE 3 Synthesis of Compound QA2-4
Compound QA2-3 (3.8g, 14.5 mmol) was dissolved in methylene chloride, triethylamine (5.5 ml, 42mmol) was added, and a solution of methanesulfonyl chloride (1.6 ml, 21.75mmol) in 10ml of DCM was slowly added to the reaction solution through a titration funnel under ice bath. The reaction was carried out at room temperature and the reaction was completed by TLC. Quenched with saturated sodium bicarbonate solution, extracted with DCM, washed with saturated sodium chloride and dried over anhydrous sodium sulfate. Filtering, and concentrating the filtrate to obtain a crude product. The compound QA2-4 (2.98 g) was purified by means of a silica gel column chromatography to obtain a white powder with a yield of 85%.
HRMS(ESI):m/z calcd.C 12 H 18 NaO 5 [M+Na] + :265.1052,found 265.1053.
EXAMPLE 4 Synthesis of Compound QA2-5
Compound QA2-4 (3.26g, 12mmol) was dissolved in 50ml of THF, and 50ml of sodium hydrogen carbonate solution (1M), imidazole (0.9g, 13.2mmol), and paraformaldehyde (720mg, 24mmol) were added. React for 2h at room temperature, and then 50mL of multiplied by 3 ethyl acetate is added for extraction, and the crude product is obtained by concentration. Compound QA2-5 (2.78 g) was obtained by purification through silica gel column chromatography as a white powder with a yield of 85%. HRMS (ESI) m/z calcd.C 13 H 20 NaO 6 [M+Na] + :295.1158,found 295.1175
EXAMPLE 5 Synthesis of QA2-6
QA2-5 (3.32g, 12mmol) was dissolved in 50ml of DCM, and triethylamine (1.3ml, 24mmol), DMAP (150mg, 1.2mmol), benzoyl chloride (2.1ml, 18mmol) were added in this order. The reaction was carried out at room temperature for 1h, quenched with saturated sodium bicarbonate solution, extracted with DCM (50 mL. Times.3), washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. Filtering, and concentrating the filtrate to obtain a crude product. Purification by silica gel column chromatography gave compound QA2-6 (4.5 g) as a white powder in 98% yield.
HRMS(ESI):m/z calcd.C 20 H 24 NaO 7 [M+Na] + :399.1420,found 399.1440.
Example 6 Synthesis of QA2-7
QA2-6 (3.76g, 10mmol) was dissolved in 50ml of THF, 50ml of water was added, and while stirring, AD-mix-a (1g, equiv, 0.1g/mmol) was added, and the reaction was carried out at room temperature for 7 hours, and quenched by addition of a saturated sodium thiosulfate solution, extracted with ethyl acetate, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. Filtering, and concentrating the filtrate to obtain a crude product. Purification by silica gel column chromatography gave compound QA2-7 (2.66 g) as a white powder in 65% yield.
HRMS(ESI):m/z calcd.C 20 H 26 NaO 9 [M+Na] + :433.1475,found 433.1499
EXAMPLE 7 Synthesis of Compounds QA2-8
Compound QA2-7 (2g, 5 mmol) was dissolved in 20ml DCM at 0 deg.C, N 2 A solution of triphosgene (2.2g, 7.5 mmol) in 20mL DCM and triethylamine (1.5mL, 10mmol) were added under protection and reacted at rt for 0.5h. Quenched by addition of saturated sodium bicarbonate solution, (30 mL. Times.3) extracted, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. Filtering, and concentrating the filtrate to obtain a crude product. Purification by silica gel column chromatography (petroleum ether: ethyl acetate, volume ratio 3).
HNMR(600MHz,CDCl 3 )δ8.01-8.00(m,2H),7.65(m,1H),7.49(m,2H),4.91(d,J＝8.4Hz,1H),4.67(d,J＝12.3Hz,1H),4.60(d,J＝12.2Hz,1H),4.08(td,J＝11.2,6.6Hz,1H),3.94(dd,J＝11.1,8.5Hz,1H),3.34(s,3H),3.28(s,3H),3.02(dd,J＝18.6,6.5Hz,1H),2.78(dd,J＝18.6,11.3Hz,1H),1.38(s,3H),1.34(s,3H). 13 CNMR(150MHz,CDCl 3 )δ196.85(s),168.61(s),167.51(s),134.11(s),129.88(s),128.78(s),128.17(s),99.57(s),99.44(s),83.02(s),78.33(s),72.09(s),64.47(s),60.48(s),48.47(s),41.25(s),17.50(s),17.43(s).HRMS(ESI):m/z calcd.C 21 H 24 NaO 10 [M+Na] + :459.1267,found 459.1292.
EXAMPLE 8 Synthesis of Compounds QA2-11 and QA2-12
Compound QA2-8 (2g, 5mmol) was dissolved in 20ml DCM, and 3ml TFA: H was added 2 O (6. Quenched by addition of saturated sodium bicarbonate solution, (30 mL. Times.3) extracted with ethyl acetate, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. Filtering, and concentrating the filtrate to obtain a crude product. Purification by silica gel column chromatography was carried out with (DCM: methanol, vol 20).
Adding compound QA2-11 (800mg, 2.7 mmol) into a sealed tube, dissolving in 10ml benzene, adding DBU (228 μ L,1.5 mmol), sealing at 100 deg.C for reaction for 12 hr, and concentrating the reaction solution to obtain crude product. Purification by silica gel column chromatography (DCM: methanol, 10 vol..
Compound QA2-11: 1 HNMR(600MHz,CDCl 3 )δ7.94(d,J＝7.6Hz,2H),7.54(s,1H),7.40(t,J＝7.6Hz,2H),4.93(s,1H),4.70(d,J＝12.3Hz,1H),4.64(d,J＝12.6Hz,1H),4.46(s,1H),4.25(s,1H),3.98(s,1H),3.13–3.10(m,1H),2.77–2.74(m,1H). 13 CNMR(150MHz,CDCl 3 )δ200.24(s),165.92(s),133.96(s),129.82(s),128.73(s),128.39(s),82.27(s),82.02(s),68.64(s),67.92(s),64.38(s),41.51(s).HRMS(ESI):m/z calcd.C 14 H 16 NaO 7 [M+Na] + :319.0794,found 319.0803
compound QA2-12: 1 HNMR(600MHz,CDCl 3 )δ7.98(d,J＝7.6Hz,2H),7.57(d,J＝7.3Hz,1H),7.43(t,J＝7.6Hz,2H),6.92(dd,J＝10.2,2.5Hz,1H),6.17(d,J＝10.2Hz,1H),4.79(d,J＝11.3Hz,1H),4.70(s,1H),4.59(d,J＝11.3Hz,1H),3.97(d,J＝4.7Hz,1H),3.63(s,1H),3.48–3.42(m,1H). 13 CNMR(150MHz,CDCl 3 )δ195.33(s),166.94(s),147.88(s),133.68(s),129.91(s),129.01(s),128.56(s),126.96(s),74.08(s),68.00(s),64.12(s).HRMS(ESI):m/z calcd.C 14 H 14 NaO 6 [M+Na] + :301.0688,found 301.0703
EXAMPLE 9 Synthesis of Compounds QA2-13
Compound QA2-12 (900mg, 3.2mmol) was dissolved in 10ml of acetone, and p-toluenesulfonic acid monohydrate (55mg, 0.3mmol), 2-dimethoxypropane (620. Mu.L) were added and reacted at room temperature for 2 hours. The reaction solution is concentrated to obtain a crude product. Purification by silica gel column chromatography gave compound QA2-13 (890 mg) as a white solid in 88% yield.
1 HNMR(600MHz,CDCl 3 )δ8.01(d,J＝7.7Hz,2H),7.61(t,J＝7.3Hz,1H),7.47(t,J＝7.5Hz,2H),7.00(dd,J＝10.0,4.6Hz,1H),6.26(d,J＝10.2Hz,1H),4.71(d,J＝11.6Hz,2H),4.58(d,J＝11.5Hz,1H),4.54(s,1H),2.68(s,1H),1.47(s,3H),1.39(s,3H). 13 CNMR(150MHz,CDCl 3 )δ195.95(s),166.11(s),145.71(s),133.69(s),129.73(s),128.69(s),128.63(s),109.61(s),80.36(s),79.87(s),64.67(s),64.54(s),27.42(s),26.34(s).HRMS(ESI):m/z calcd.C 17 H 18 NaO 6 [M+Na] + :341.1001,found 341.1015.
EXAMPLE 10 Synthesis of Compounds QA2-14
Compound QA2-13 (850mg, 2.7mmol) was dissolved in 5ml of DCM, triethylamine (0.6ml, 4mmol), DMAP (25mg, 0.2mmol), benzoyl chloride (360. Mu.L, 3 mmol). Reaction at room temperature for 1h, saturated sodium bicarbonate, quenched (10 mL. Times.3) with DCM, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. Filtering, and concentrating the filtrate to obtain a crude product. The compound QA2-14 (1.0 g) was purified by means of a silica gel column chromatography to obtain white powders with respective yields of 95%.
1 HNMR(600MHz,CDCl 3 )δ7.97(d,J＝7.9Hz,2H),7.88(d,J＝7.9Hz,2H),7.53(ddd,J＝10.5,9.9,4.0Hz,2H),7.39(dd,J＝11.0,4.3Hz,2H),7.31(d,J＝7.5Hz,2H),7.09(ddd,J＝10.0,4.8,1.7Hz,1H),6.41(d,J＝10.2Hz,1H),6.00(d,J＝4.8Hz,1H),4.72(m,2H),4.62(d,J＝12.0Hz,1H),1.51(s,3H),1.44(s,3H). 13 CNMR(150MHz,CDCl 3 )δ195.61(s),165.67(s),165.25(s),141.49(s),133.68(s),133.41(s),130.68(s),129.77(s),129.72(s),129.14(s),128.50(s),128.48(s),110.07(s),80.02(s),77.70(s),65.99(s),63.91(s),27.41(s),26.42(s).HRMS(ESI):m/z calcd.C 24 H 22 NaO 7 [M+Na] + :445.1263,found 445.1291
EXAMPLE 11 Synthesis of + (-) zealenone
Compound QA2-14 (1.0 g,2.3 mmol) was dissolved in 5ml of methanol, and 2ml of 1N diluted hydrochloric acid was added. Reacting at room temperature for 1h, saturating sodium bicarbonate, and concentrating the reaction solution to obtain a crude product. Purification by silica gel column chromatography (petroleum ether: ethyl acetate, volume ratio 2.
1 HNMR(500MHz,CDCl 3 )δ8.03–8.01(m,2H),7.94–7.93(m,2H),7.56(dt,J＝10.2,7.5Hz,2H),7.42(dt,J＝16.0,7.9Hz,4H),6.97(ddd,J＝10.2,4.1,1.2Hz,1H),6.35(d,J＝10.2Hz,1H),5.96(t,J＝3.7Hz,1H),4.85(d,J＝11.5Hz,1H),4.60(d,J＝11.5Hz,1H),4.38(s,1H),4.09(s,1H,OH),3.20(d,J＝2.4Hz,OH). 13 CNMR(125MHz,CDCl 3 )δ196.42(s),166.37(s),165.48(s),142.85(s),133.98(s),133.63(s),129.97(s),129.90(s),128.84(s),128.73(s),128.63(s),71.80(s),69.31(s),65.61(s).HRMS(ESI):m/z calcd.C 21 H 18 NaO 7 [M+Na] + :405.0950,found 405.0972
EXAMPLE 12 Synthesis of Compounds QA2-15
Compound QA2-7 (433mg, 1mmol) was dissolved in 3ml of DCM, triethylamine (0.9ml, 1.5mmol), DMAP (12mg, 0.1mmol), acetyl chloride (0.18ml, 2.5mmol). The reaction was carried out at room temperature, checked by TLC dot plate, and when the reaction reached one major product point, the reaction was terminated, saturated sodium bicarbonate, quenched (30 mL. Times.3) by DCM extraction, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. Filtering, and concentrating the filtrate to obtain a crude product. The compound QA2-15 (500 mg) was obtained as a white powder by purification through silica gel column chromatography, with yields of 90% respectively.
1 HNMR(600MHz,CDCl 3 )δ8.02–8.01(m,2H),7.59(d,J＝7.3Hz,1H),7.48(m,2H),5.33–5.32(m,1H),4.78(d,J＝11.6Hz,1H),4.71(d,J＝11.6Hz,1H),4.26(t,J＝10.1Hz,1H),3.85(ddd,J＝13.0,9.9,5.2Hz,1H),3.32(s,3H),3.24(s,3H),2.91(t,J＝13.0Hz,1H),2.70(dd,J＝12.9,5.2Hz,1H),2.21(s,3H),2.06(s,3H),1.28(s,3H),1.24(s,3H). 13 CNMR(150MHz,CDCl 3 )δ198.88(s),169.97(s),169.51(s),165.84(s),133.50(s),129.94(s),128.64(s),100.05(s),100.00(s),82.88(s),70.58(s),69.46(s),64.64(s),62.48(s),48.29(s),48.07(s),41.65(s),20.82(s),20.76(s),17.79(s),17.77(s).HRMS(ESI):m/z calcd.C 24 H 30 NaO 11 [M+Na] + :517.1686,found 517.1682.
EXAMPLE 13 Synthesis of Compounds QA2-16
Compound QA2-15 (400g, 0.7 mmol) was dissolved in 2ml DCM and TFA H was added 2 O (9. The reaction was carried out at room temperature for 1 hour, neutralized with saturated sodium bicarbonate, (5 mL. Times.3) extracted with DCM, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. Filtering, and concentrating the filtrate to obtain a crude product. The compound QA2-16 (250 mg) was obtained by purification through silica gel column chromatography as a white powder with a yield of 94% respectively.
1 HNMR(600MHz,CDCl 3 )δ7.98(d,J＝8.2Hz,2H),7.55(d,J＝7.3Hz,1H),7.42(d,J＝7.3Hz,2H),5.29–5.27(m,1H),4.75(d,J＝11.0Hz,1H),4.67(d,J＝11.6Hz,1H),4.22(t,J＝10.1Hz,1H),3.80(m,1H),2.87(t,J＝13.0Hz,1H),2.67(dd,J＝12.9,5.5Hz,1H),2.16(s,3H),2.03(s,3H). 13 CNMR(150MHz,CDCl 3 )δ198.73(s),169.82(s),169.35(s),165.68(s),133.35(s),129.78(s),129.41(s),128.48(s),82.73(s),70.42(s),69.31(s),64.49(s),62.32(s),41.50(s),20.66(s),20.61(s).HRMS(ESI):m/z calcd.C 18 H 20 NaO 8 [M+Na] + :517.1687,found 517.1682.
EXAMPLE 14 Synthesis of Compounds QA2-17 and Compounds QA2-18
Compound QA2-16 (200mg, 0.6 mmol) was dissolved in 2mL DCM, DIPEA (200. Mu.L, 1.2 mmol) and methylsulfonyl chloride (46. Mu.L, 0.6 mmol) were added, reacted at room temperature for 1h, neutralized and quenched with saturated sodium bicarbonate, (3 mL. Times.3) DCM extracted, washed with saturated sodium chloride, dried over anhydrous sodium sulfate. Filtering, and concentrating the filtrate to obtain a crude product. Purifying by silica gel column chromatography. Purification by silica gel column chromatography gave compound QA2-18 (110 mg) in 42% yield as a white powder and compound QA2-17 (50 mg) in 23% yield as a white powder.
QA2-17: 1 HNMR(600MHz,CDCl 3 )δ7.97(d,J＝7.1Hz,2H),7.59(d,J＝6.6Hz,1H),7.46-7.43(m,2H),6.91(d,J＝10.3Hz,1H),6.25(d,J＝10.3Hz,1H),5.49(d,J＝7.7Hz,1H),4.86(d,J＝10.2Hz,2H),4.61(d,J＝10.6Hz,1H),2.18(s,3H),2.15(s,3H). 13 CNMR(150MHz,CDCl 3 )δ190.52(s),171.04(s),169.49(s),165.56(s),148.25(s),133.58(s),129.92(d,J＝8.3Hz),129.89(s),128.66(s),128.14(s),80.20(s),74.82(s),68.98(s),62.23(s),20.92(s),20.71(s).HRMS(ESI):m/z calcd.C 18 H 18 NaO 8 [M+Na] + :385.0899,found385.0899.
QA2-18: 1 HNMR(600MHz,CDCl 3 )δ7.94(dd,J＝8.2,1.1Hz,2H),7.59-7.55(m,1H),7.45(s,2H),6.86(dd,J＝10.6,1.9Hz,1H),6.33(dd,J＝10.6,2.2Hz,1H),5.77(dt,J＝8.1,2.1Hz,1H),5.73(d,J＝8.1Hz,1H),4.79(d,J＝10.9Hz,1H),4.55(d,J＝10.9Hz,1H),3.08(s,3H),2.15(s,3H),2.14(s,3H). 13 CNMR(150MHz,CDCl 3 )δ189.81(s),169.72(s),169.67(s),165.40(s),142.68(s),133.63(s),130.11(s),129.90(d,J＝7.2Hz),129.21(s),128.67(s),79.84(s),75.25(s),70.89(s),62.44(s),38.83(s),20.76(s),20.57(s).HRMS(ESI):m/z calcd.C 19 H 20 NaO 10 S[M+Na] + :463.0675,found 463.0673
EXAMPLE 15 Synthesis of Compounds QA2-19
Compound QA2-17 (30mg, 0.083mmol) was dissolved in 1ml DCM, triethylamine (15. Mu.L, 0.15 mmol), DMAP (1mg, 0.01mmol), benzoyl chloride (8. Mu.L, 0.1 mmol). The reaction was carried out at room temperature for 1h, saturated sodium bicarbonate, quenched (3 mL. Times.3) by extraction with DCM, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. Filtering, and concentrating the filtrate to obtain a crude product. The compound QA2-19 (35 mg) was obtained as a white powder by purification through silica gel column chromatography, with a yield of 95% each.
1 HNMR(500MHz,CDCl 3 )δ7.98(m,4H),7.55(t,J＝7.6Hz,2H),7.00(m,4H),6.88-6.86(m,1H),6.32(d,J＝10.3,1H),6.17-6.16(m,1H),5.93(dd,J＝4.4,0.8Hz,1H),4.88(d,J＝,11.4Hz,1H),4.62(d,J＝,11.4Hz,1H),2.17(s,3H),2.00(s,3H). 13 CNMR(125MHz,CDCl 3 )δ190.14(s),169.58(s),169.56(s),165.94(s),165.60(s),143.82(s),133.94(s),133.55(s),129.92(s),129.37(s),129.30(s),128.94(s),128.83(s),128.65(s),80.78(s),71.35(s),70.78(s),61.69(s),20.76(s),20.67(s).HRMS(ESI):m/z calcd.C 25 H 22 NaO 9 [M+Na] + :489.1162,found 489.1158
EXAMPLE 16 Synthesis of Compounds QA1-6
The- (-) zearylone (1g, 3.3 mmol) was dissolved in 20ml of methanol, and the Zanthoxylone standard was provided by the institute of medicinal plants of Kyoho institute of medicine and identified by NMR mass spectrometry CD. 10ml of ammonia water is added, and the reaction is carried out for 4 hours at 80 ℃ under the condition of tube sealing and reflux. The reaction mixture was concentrated and purified by silica gel column chromatography to give Compound QA1-6 (410 mg) as a white powder in a yield of 45% respectively.
1 HNMR(600MHz,CDCl 3 )δ7.97(d,J＝7.5Hz,1H),7.57(t,J＝7.3Hz,1H),7.44(t,J＝7.5Hz,1H),6.92(dd,J＝10.2,2.5Hz,1H),6.16(d,J＝10.2Hz,1H),4.79(d,J＝10.8Hz,1H),4.69(s,1H),4.58(d,J＝11.3Hz,1H),3.96(d,J＝4.7Hz,1H),3.62(s,1H),3.47(s,1H). 13 CNMR(150MHz,CDCl 3 )δ195.47(s),167.08(s),148.02(s),133.82(s),130.05(s),129.15(s),128.70(s),127.10(s),76.43(s),74.22(s),68.14(s),64.26(s).HRMS(ESI):m/z calcd.C 14 H 14 NaO 6 [M+Na] + :301.0688,found 301.0719.
EXAMPLE 17 Synthesis of Compounds QA1-7
Compound QA1-6 (400mg, 1.44mmol) was dissolved in 10ml of acetone, p-toluenesulfonic acid monohydrate (20mg, 0.13mmol) and 2, 2-dimethoxypropane (280. Mu.L, 2 mmol) were added, and the reaction solution was concentrated to obtain a crude product. Purification by silica gel column chromatography gave compound QA1-7 (371 mg) as a white solid in 88% yield.
1 HNMR(600MHz,CDCl 3 )δ8.00(dd,J＝23.4,7.7Hz,2H),7.59(t,J＝7.3Hz,1H),7.45(t,J＝7.5Hz,2H),6.98(dd,J＝10.0,4.6Hz,1H),6.23(d,J＝10.2Hz,1H),4.68(d,J＝11.6Hz,2H),4.56(d,J＝11.2Hz,1H),4.51(s,1H),1.45(s,3H),1.36(s,3H). 13 CNMR(150MHz,CDCl 3 )δ196.10(s),166.25(s),145.86(s),133.84(s),129.87(s),128.83(s),128.77(s),109.76(s),80.51(s),80.02(s),64.82(s),64.69(s),27.57(s),26.49(s).HRMS(ESI):m/z calcd.C 17 H 18 NaO 6 [M+Na] + :341.1001,found 341.1007
EXAMPLE 18 Synthesis of Compounds QA1-8
Compound QA2-13 (210mg, 0.7 mmol) was dissolved in 2ml DCM, triethylamine (0.6 ml, 1mmol), DMAP (4 mg, 0.05mmol), benzoyl chloride (90. Mu.L, 0.75 mmol). Reaction at room temperature for 1h, saturated sodium bicarbonate, quenched (3 mL. Times.3) by DCM extraction, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. Filtering, and concentrating the filtrate to obtain a crude product. The compound QA1-8 (570 mg) was purified by silica gel column chromatography to obtain white powders with yields of 93%, respectively.
1 HNMR(600MHz,CDCl 3 )δ7.94(d,J＝7.9Hz,2H),7.84(d,J＝7.9Hz,2H),7.51(dd,J＝6.7,5.5Hz,2H),7.35(m,2H),7.28(d,J＝7.5Hz,2H),7.06(m,1H),6.38(d,J＝12.0Hz,1H),5.97(d,J＝4.7Hz,1H),4.70(d,J＝11.6Hz,1H),4.68(s,1H),4.62(d,J＝11.7Hz,1H),1.48(s,3H),1.40(s,3H). 13 CNMR(150MHz,CDCl 3 )δ195.61(s),165.67(s),165.25(s),141.49(s),133.68(s),133.41(s),130.68(s),129.77(s),129.72(s),129.14(s),128.50(s),128.48(s),110.07(s),80.02(s),77.70(s),65.99(s),63.91(s),27.41(s),26.42(s).HRMS(ESI):m/z calcd.C 24 H 22 NaO 7 [M+Na] + :445.1263,found 445.1266
EXAMPLE 19 Synthesis of Compound Zey-B1
Compound QA2-13 (50mg, 0.15mmol), DMAP, (2.0 mg, 0.015mmol), DCC (61mg, 0.3mmol) was dissolved in 1ml DCM and p-fluorobenzoic acid (280mg, 0.2mmol) was reacted at room temperature for 12 hours. After evaporation, 2mL of ether was added, the mixture was filtered, and the filtrate was concentrated to give a crude product. Purification by silica gel column chromatography gave compound Zey-B1 (60 mg) as a white powder in 90% yield.
1 HNMR(600MHz,298K,CDCl 3 ):δ(ppm)＝7.93(dd,J＝8.2,1.2Hz,2H,Ar-H),7.88-7.82(m,2H,Ar-H),7.56-7.50(m,1H,Ar-H),7.37(t,J＝7.8Hz,2H,Ar-H),7.04(ddd,J＝10.2,4.9,1.8Hz,1H,H-4),6.98-6.88(m,2H,Ar-H),6.39(d,J＝10.2Hz,1H,H-5),5.94(dd,J＝4.9,1.2Hz,1H,H-3),4.69-4.62(m,3H,H-2,H-7a,7b),1.48(s,3H,Me),1.41(s,3H,Me). 13 CNMR(150MHz,CDCl 3 ):δ(ppm)＝195.7(s,C-1),166.8(d,J C-F ＝253.9.Hz,C-F),166.4(s,C＝O),164.6(s,C＝O),141.5(s,C-4),133.7(s,Ar-C),132.6(s,Ar-C),132.6(s,Ar-C),130.9(s,C-5),129.8(s,2Ar-C)),129.2(s,Ar-C),128.7(s,2Ar-C),124.9(s,Ar-C),115.9(s,Ar-C),115.8(s,Ar-C),110.2(s,CO 2 (Me) 2 ),80.1(s,C-2),77.8(s,C-1),66.3(s,C-3),64.1(s,C-7),27.6(s,Me),26.6(s,Me).
HRMS(ESI):m/z calcd.C 24 H 21 FNaO 7 [M+Na] + :463.1169,found 463.1195
EXAMPLE 20 Synthesis of Compound ZEY-B2
According to the synthesis method of the compound Zey-B1, p-methoxybenzoic acid is used instead. Compound Zey-B2 (65 mg) was obtained in 92% yield as a white powder.
1 HNMR(600MHz,298K,CDCl 3 ):δ(ppm)＝7.95(d,J＝7.2Hz,2H,Ar-H),7.80(d,J＝8.9Hz,2H,Ar-H),7.53(t,J＝7.4Hz,1H,Ar-H),7.37(t,J＝7.8Hz,2H,Ar-H),7.05(ddd,J＝10.2,4.9,1.8Hz,1H,H-4),6.74(d,J＝8.9Hz,2H,Ar-H),6.37(d,J＝10.2Hz,1H,H-5),5.94(dd,J＝4.9,1.2Hz,1H,H-3),4.69(d,J＝11.8Hz,1H,H-7a),4.67(t,J＝1.7Hz,1H,H-7b),4.62(d,J＝11.8Hz,1H,H-2),3.81(s,3H,OMe),1.48(s,3H,Me),1.41(s,3H,Me). 13 CNMR(150MHz,CDCl 3 ):δ(ppm)＝195.8(s,C-1),165.9(s,C＝O),165.1(s,C＝O),164.0(s,C＝C(OMe)),142.0(s,C-4),133.6(s,Ar-C),132.1(s,2×Ar-C),132.1(s,2×Ar-C),130.7(s,C-5),129.9(s,2×Ar-C),129.3(s,Ar-C),128.6(s,2×Ar-C),120.9(s,Ar-C),113.9(s,2×Ar-C),110.1(s,CO 2 (Me) 2 ),80.2(s,C-2),77.8(s,C-1),65.8(s,C-3),64.0(s,C-7),55.6(s,OMe),27.6(s,Me),26.6(s,Me).
HRMS(ESI):m/z calcd.C 25 H 24 NaO 8 [M+Na] + :475.1369,found 475.1390
EXAMPLE 21 Synthesis of Compound ZEY-B3
According to the synthesis method of the compound Zey-B1, p-methylbenzoic acid is used instead. Compound Zey-B3 (55 mg) was obtained as a white powder in 85% yield.
1 HNMR(600MHz,298K,CDCl 3 ):δ(ppm)＝7.95(dd,J＝8.3,1.1Hz,2H,Ar-H),7.73(d,J＝8.2Hz,2H,Ar-H),7.52(t,J＝7.5Hz,1H,Ar-H),7.36(t,J＝7.8Hz,2H,Ar-H),7.07(d,J＝7.9Hz,2H,Ar-H),7.05-7.03(m,1H,H-4),6.37(d,J＝10.2Hz,1H,H-5),5.95(dd,J＝4.8,1.2Hz,1H,H-3),4.70(d,J＝11.8Hz,1H,H-7a),4.68(t,J＝1.7Hz,1H,H-7b),4.61(d,J＝11.8Hz,1H,H-2),2.35(s,3H,Me-Ph),1.48(s,3H,Me),1.41(s,3H,Me).
13 CNMR(150MHz,CDCl 3 ):δ(ppm)＝195.8(s,C-6),165.8(s,C＝O),165.4(s,C＝O),144.7(s,C-4),141.8(s,C＝CMe),133.5(s,Ar-C),130.7(s,C-5),130.0(s,2×Ar-C),129.9(s,2×Ar-C),129.4(s,2×Ar-C),129.3(s,Ar-C),128.6(s,2×Ar-C),125.9(s,Ar-C),110.2(s,CO 2 (Me) 2 ),80.2(s,C-2),77.8(s,C-1),65.9(s,C-3),64.0(s,C-7),27.6(s,Me),26.6(s,Me),21.9(s,Ar-Me)；
HRMS(ESI):m/z calcd.C 22 H 20 NaO 8 [M+Na] + :435.1056,found 435.1080.
EXAMPLE 22 Synthesis of Compound ZEY-B4
According to the synthesis method of the compound Zey-B1, the compound Zey-B4 (58 mg) was obtained as a white powder with a yield of 87% by replacing cyclohexanecarboxylic acid with cyclohexanecarboxylic acid.
1 HNMR(600MHz,298K,CDCl 3 ):δ(ppm)＝7.99(dd,J＝8.3,1.2Hz,2H,Ar-H),7.58(t,J＝7.4Hz,1H,Ar-H),7.44(t,J＝7.8Hz,2H,Ar-H),6.82(ddd,J＝10.2,4.2,1.4Hz,1H,H-4),6.28(dd,J＝10.2,0.8Hz,1H,H-5),5.69(dd,J＝5.3,2.0Hz,1H,H-3),4.71(d,J＝11.6Hz,1H,H-7a),4.52(d,J＝11.6Hz,1H,H-7b),4.18(dd,J＝3.2,1.4Hz,1H,H-2),2.02-2.01(m,1H,CHCO(CH 2 ) 2 ),1.70-1.67(m,2H,H of cyclohexyl),1.67-1.60(m,2H,H of cyclohexyl),1.54(s,3H,Me),1.45(s,3H,Me),1.28-1.24(m,3H,H of cyclohexyl),1.07-1.05(m,3H,H of cyclohexyl).
13 CNMR(150MHz,CDCl 3 ):δ(ppm)＝195.9(s,C-1),174.8(s,C＝O),165.7(s,C＝O),141.8(s,C-4),133.6(s,Ar-C),130.7(s,C-5),129.9(s,2×Ar-C),129.4(s,Ar-C),128.7(s,2×Ar-C),110.1(s,CO 2 (Me) 2 ),80.0(s,C-2),77.9(s,C-1),64.9(s,C-3),64.0(s,C-7),42.8(s,C of cyclohexyl),29.0(s,C of cyclohexyl),28.9(s,C of cyclohexyl),27.5(s,Me),26.5(s,Me),25.6(s,C of cyclohexyl),25.3(s,C of cyclohexyl),25.3(s,C of cyclohexyl)；
HRMS(ESI):m/z calcd.C 24 H 28 NaO 7 [M+Na] + :451.1733,found 451.1731.
EXAMPLE 23 Synthesis of Compound ZEY-B5
According to the synthesis method of the compound Zey-B1, phenylpropionic acid is used to obtain the compound Zey-B5 (60 mg) as white powder with the yield of 85 percent.
1 HNMR(600MHz,298K,CDCl 3 ):δ(ppm)＝7.97(dd,J＝8.3,1.2Hz,2H,Ar-H),7.57-7.52(m,1H,Ar-H),7.40(t,J＝7.8Hz,2H,Ar-H),7.24(t,J＝7.3Hz,2H,Ar-H),7.21-7.18(m,1H,Ar-H),7.02(d,J＝7.1Hz,2H,Ar-H),6.82(ddd,J＝10.2,5.0,1.8Hz,1H,H-4),6.30(d,J＝10.3Hz,1H,H-5),5.68(dd,J＝5.0,1.4Hz,1H,H-3),4.60(d,J＝11.5Hz,1H,H-7a),4.51(d,J＝11.5Hz,1H,H-7b),4.34(t,J＝1.8Hz,1H,H-2),2.80(t,J＝7.7Hz,2H,CH 2 CH 2 -Ph),2.42(dt,J＝15.7,7.8Hz,1H,CH 2 CH 2 -Ph),2.35-2.32(m,1H,CH 2 CH 2 -Ph),1.44(s,3H,Me),1.36(s,3H,Me)；
13 CNMR(150MHz,CDCl 3 ):δ(ppm)＝196.0(s,C-1),171.7(s,C＝O),166.1(s,C＝O),142.9(s,C-4),142.9(s,Ar-C),139.8(s,Ar-C),133.6(s,2×Ar-C),129.8(s,Ar-C),129.2(s,2×Ar-C)),128.6(s,2×Ar-C),128.6(s,2×Ar-C),128.3(s,C-5),126.5(s,Ar-C),109.9(s,CO 2 (Me) 2 ),80.1(s,C-2),78.1(s,C-1),65.1(s,C-3),64.1(s,C-7),35.6(s,CH 2 ),30.9(s,CH 2 ),27.5(s,Me),26.5(s,Me)；
HRMS(ESI):m/z calcd.C 26 H 26 NaO 7 [M+Na] + :473.1576,found 473.1604
EXAMPLE 24 Synthesis of Compound ZEY-B6
According to the synthesis method of the compound Zey-B1, phenylacetic acid is used instead, and the compound Zey-B6 (55 mg) is obtained as white powder with the yield of 85%. [ alpha ] to] 20 D＝-22.5(c＝0.5,CHCl 3 )。
1 HNMR(600MHz,298K,CDCl3):δ(ppm)＝8.01(dd,J＝8.2,1.1Hz,2H,Ar-H),7.60(t,J＝7.5Hz,1H,Ar-H),7.46(t,J＝7.8Hz,2H,Ar-H),7.21-7.20(m,2H,Ar-H),7.08(dd,J＝7.4,1.7Hz,2H,Ar-H),6.90(ddd,J＝10.2,5.0,1.8Hz,1H,H-4),6.33(d,J＝10.2Hz,1H,H-5),5.70(dd,J＝5.0,1.6Hz,1H,H-3),4.68(d,J＝11.7Hz,1H,H-7a),4.47(t,J＝1.8Hz,1H,H-2),4.44(d,J＝11.7Hz,1H,H-7b),3.41(dd,J＝37.7,15.4Hz,2H,CH 2 -Ph),1.43(s,3H,Me),1.35(s,3H,Me)；
13 CNMR(150MHz,CDCl 3 ):δ(ppm)＝195.7(s,C-6),170.4(s,C＝O),165.7(s,C＝O),141.3(s,C-4),133.7(s,Ar-C),133.0(s,Ar-C),131.0(s,C-5),130.0(s,2×Ar-C),129.5(s,Ar-C),129.3(s,2×Ar-C),128.8(s,2×Ar-C),128.8(s,2×Ar-C),127.6(s,Ar-C),110.2(s,CO 2 (Me) 2 ),80.0(s,C-2),77.5(s,C-1),65.7(s,C-3),63.7(s,C-7),40.8(s,CH 2 (CO)Ar),27.5(s,Me),26.5(s,Me)；
HRMS(ESI):m/z calcd.C 22 H 20 NaO 7 [M+Na] + :459.1420,found 459.1446
EXAMPLE 25 Synthesis of Compound Zey-A1
The compound Zey-B1 (30mg, 0.65mmol) was dissolved in 1m THF, 1ml 1N diluted hydrochloric acid was added, and the reaction was carried out at room temperature for 1 hour. The mixture was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (2 mL. Times.3), washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. Filtering, and concentrating the filtrate to obtain a crude product. Purification by silica gel column chromatography (petroleum ether: ethyl acetate, volume ratio 2: 1) gave compound Zey-A1 (21 mg) as a white powder in 79% yield.
1 HNMR(600MHz,298K,CDCl 3 ):δ(ppm)＝8.03-8.01(m,2H,Ar-H),7.93-7.92(m,2H,Ar-H),7.56(t,J＝7.4Hz,1H,Ar-H),7.41(t,J＝7.8Hz,2H,Ar-H),7.08(t,J＝8.6Hz,2H,Ar-H),6.95(ddd,J＝10.2,4.1,1.2Hz,1H,H-4),6.34(d,J＝10.2Hz,1H,H-5),5.94(m,1H,H-3),4.80(d,J＝11.5Hz,1H,H-7a),4.59(d,J＝11.5Hz,1H,H-7b),4.37(s,1H,H-2),4.10(s,OH),3.24(s,OH).
13 CNMR(150MHz,CDCl 3 ):δ(ppm)＝196.3(s,C-1),166.8(d,J C-F ＝253.5.Hz,C-F),166.4(s,C＝O),164.6(s,C＝O),142.8(s,C-4),133.7(s,Ar-C),132.6(s,Ar-C),132.6(s,Ar-C),129.9(s,2×Ar-C)),129.2(s,Ar-C),128.8(s,C-5),128.6(s,2×Ar-C),125.1(s,Ar-C),116.1(s,Ar-C),116.0(s,Ar-C),77.4(s,C-2),71.7(s,C-1),69.5(s,C-3),65.5(s,C-7).
HRMS m/z calcd.C 21 H 17 FNaO 7 [M+Na] + :423.0857,found 423.0856
EXAMPLE 26 Synthesis of Compound Zey-A2
Zey-B2 was hydrolyzed according to the method for synthesizing Zey-A1 to obtain Zey-A2 (20 mg) as a white powder with a yield of 75%.
1 HNMR(600MHz,298K,CDCl 3 ):7.96(d,J＝9.0Hz,2H,Ar-H),7.94(dd,J＝8.3,1.2Hz,2H,Ar-H),7.55(t,J＝7.4Hz,1H,Ar-H),7.41(dd,J＝8.1,7.6Hz,2H,Ar-H),6.96(ddd,J＝10.2,4.2,1.5Hz,1H,H-4),6.89(d,J＝9.0Hz,2H,Ar-H),6.33(dd,J＝10.2,0.9Hz,1H,H-5),5.95-5.90(m,1H,H-3),4.84(d,J＝11.5Hz,1H,H-7a),4.59(d,J＝11.5Hz,1H,H-7b),4.36(dd,J＝3.3,1.5Hz,1H,H-2),4.11(s,OH),3.85(s,3H,OMe),3.18(s,OH).
13 CNMR(150MHz,CDCl 3 ):δ(ppm)＝196.6(s,C-6),166.3(s,C＝O),165.2(s,C＝O),164.1(s,C＝C(OMe)),143.1(s,C-4),139.9(s,Ar-C),133.6(s,Ar-C),132.1(s,2×Ar-C),129.9(s,2×Ar-C),129.3(s,Ar-C),128.6(s,2×Ar-C),128.6(s,C-5),121.1(s,Ar-C),114.1(s,2×Ar-C),77.4(s,C-2),71.8(s,C-1),69.0(s,C-3),65.7(s,C-7),55.7(s,OMe).
HRMS(ESI):m/z calcd.C 22 H 20 NaO 8 [M+Na] + :435.1056,found 435.1080
EXAMPLE 27 Synthesis of Compound Zey-A3
Zey-B3 was hydrolyzed according to the method for synthesizing Zey-A1 to obtain Zey-A3 (18 mg) as a white powder with a yield of 70%.
1 HNMR(600MHz,298K,CDCl 3 ):δ(ppm)＝7.94(d,J＝7.5Hz,2H,Ar-H),7.90(d,J＝8.1Hz,2H,Ar-H),7.55(t,J＝7.4Hz,1H,Ar-H),7.41(t,J＝7.7Hz,2H,Ar-H),7.21(d,J＝8.0Hz,2H,Ar-H),6.96(dd,J＝10.1,3.9Hz,1H,H-4),6.33(d,J＝10.2Hz,1H,H-5),5.94(t,J＝3.5Hz,1H,H-3),4.84(d,J＝11.5Hz,1H,H-7a),4.59(d,J＝11.5Hz,1H,H-7b),4.37(d,J＝2.2Hz,1H,H-2),2.39(s,3H,Me-Ph).
13 CNMR(150MHz,CDCl 3 ):δ(ppm)＝196.5(s,C-6),166.3(s,C＝O),165.6(s,C＝O),144.9(s,C-4),143.0(s,C＝CMe),133.6(s,Ar-C),130.0(s,2×Ar-C),129.9(s,2×Ar-C),129.5(s,2×Ar-C),129.3(s,Ar-C),128.7(s,C-5),128.6(s,2×Ar-C),126.1(s,Ar-C),77.4(s,C-2),71.8(s,C-1),69.2(s,C-3),65.6(s,C-7),21.9(s,Ar-Me).
HRMS(ESI):m/z calcd.C 22 H 20 NaO 7 [M+Na] + :419.1107,found 419.113.
EXAMPLE 28 Synthesis of Compound Zey-A4
Zey-B4 was hydrolyzed according to the method for synthesizing Zey-A1 to obtain Zey-A4 (20 mg) as a white powder with a yield of 73%.
1 HNMR(600MHz,298K,CDCl 3 ):δ(ppm)＝7.99(dd,J＝8.3,1.2Hz,2H,Ar-H),7.58(t,J＝7.4Hz,1H,Ar-H),7.44(t,J＝7.8Hz,2H,Ar-H),6.82(ddd,J＝10.2,4.2,1.4Hz,1H,H-4),6.28(dd,J＝10.2,0.8Hz,1H,H-5),5.69(dd,J＝5.3,2.0Hz,1H,H-3),4.71(d,J＝11.6Hz,1H,H-7a),4.52(d,J＝11.6Hz,1H,H-7b),4.18(dd,J＝3.2,1.4Hz,1H,H-2),4.05(br s,OH),3.07(br s,OH),2.39-2.30(m,1H,CHCO(CH 2 ) 2 ),1.98-1.84(m,2H,H of cyclohexyl),1.77-1.63(m,3H,H of cyclohexyl),1.44(qd,J＝13.0,3.5Hz,2H,H of cyclohexyl),1.24(ddd,J＝24.6,12.2,5.8Hz,3H,H of cyclohexyl).
13 CNMR(150MHz,CDCl 3 ):δ(ppm)＝196.5(s,C-1),174.9(s,C＝O),166.3(s,C＝O),143.0(s,C-4),133.7(s,Ar-C),129.9(s,C-5),129.3(s,2×Ar-C)),128.7(s,Ar-C),128.4(s,2×Ar-C),77.3(s,C-2),71.8(s,C-1),68.4(s,C-3),65.7(s,C-7),42.1(s,C of cyclohexyl),29.1(s,C of cyclohexyl),29.1(s,C of cyclohexyl),25.7(s,C of cyclohexyl),25.4(s,2×C of cyclohexyl).
HRMS(ESI):m/z calcd.C 21 H 24 NaO 7 [M+Na] + :411.1420,found 411.1441
EXAMPLE 29 Synthesis of Compound Zey-A5
Zey-B5 was hydrolyzed according to the method for synthesizing the compound Zey-A1 to obtain a compound Zey-A5 (15 mg) as a white powder with a yield of 67%.
1 HNMR(600MHz,298K,CDCl 3 ):δ(ppm)＝8.03-7.95(m,2H,Ar-H),7.58(t,J＝7.4Hz,1H,Ar-H),7.44(t,J＝7.7Hz,2H,Ar-H),7.28(t,J＝7.5Hz,2H,Ar-H),7.20(t,J＝7.4Hz,1H,Ar-H),7.16(d,J＝7.2Hz,2H,Ar-H),6.71(dd,J＝10.2,3.9Hz,1H,H-4),6.23(d,J＝10.2Hz,1H,H-5),5.68(dd,J＝5.2,2.4Hz,1H,H-3),4.61(d,J＝11.5Hz,1H,H-7a),4.45(d,J＝11.5Hz,1H,H-7b),4.08(d,J＝3.6Hz,1H,H-2),4.08(s,OH),3.18(s,OH),2.95(dd,J＝11.7,4.5Hz,2H,CH 2 CH 2 -Ph),2.69(td,J＝7.7,3.6Hz,2H,CH 2 CH 2 -Ph).
13 CNMR(150MHz,CDCl 3 ):δ(ppm)＝196.2(s,C-1),171.9(s,C＝O),166.3(s,C＝O),143.0(s,C-4),139.9(s,Ar-C),133.7(s,Ar-C),129.9(s,2×Ar-C),129.3(s,Ar-C),128.7(s,2×Ar-C)),128.7(s,2×Ar-C),128.4(s,2×Ar-C),128.4(s,C-5),126.7(s,Ar-C),77.2(s,C-2),71.7(s,C-1),69.0(s,C-3),65.2(s,C-7),35.8(s,CH 2 ),31.0(s,CH 2 ).
HRMS(ESI):m/z calcd.C 23 H 22 NaO 7 [M+Na] + :433.1263,found 433.1275
EXAMPLE 30 Synthesis of Compound ZEY-A6
Zey-B5 was hydrolyzed according to the method for synthesizing Zey-A1 to obtain Zey-A6 (16 mg) as a white powder with a yield of 65%.
1 HNMR(600MHz,298K,CDCl 3 ):δ(ppm)＝7.98(d,J＝7.1Hz,1H,Ar-H),7.59(t,J＝7.5Hz,1H,Ar-H),7.45(dd,J＝8.1,7.6Hz,1H,Ar-H),7.35-7.28(m,1H,Ar-H),7.28-7.22(m,3H,Ar-H),6.79(ddd,J＝10.2,4.1,1.4Hz,1H,H-4),6.26(dd,J＝10.2,0.9Hz,1H,H-5),5.72-5.67(m,1H,H-3),4.61(d,J＝11.6Hz,1H,H-7a),4.35(d,J＝11.6Hz,1H,H-7b),4.14-4.09(m,1H,H-2),4.03(s,1H,OH),3.73-3.63(m,2H,CH 2 -Ph),3.10(s,1H,OH).
13 CNMR(150MHz,CDCl 3 ):δ(ppm)＝196.3(s,C-6),170.5(s,C＝O),166.2(s,C＝O),142.5(s,C-4),133.7(s,Ar-C),133.1(s,Ar-C),129.9(s,2×Ar-C),129.4(s,2×Ar-C),129.3(s,Ar-C),129.0(s,2×Ar-C),128.7(s,2×Ar-C),128.6(s,C-5),127.7(s,Ar-C),77.3(s,C-2),71.7(s,C-1),69.1(s,C-3),65.4(s,C-7),41.3(s,CH 2 (CO)Ar).
HRMS(ESI):m/z calcd.C 22 H 20 NaO 7 [M+Na] + :419.1107,found 419.1127
EXAMPLE 31 Synthesis of Compound Zey-C1 and Compound Zey-C2
After + (-) zearylone (40mg, 0.11mmol) was dissolved in 2mL of DCM, DMAP (1.5mg, 0.1mmol) and triethylamine (15. Mu.L, 0.1 mmol) were added, and acetyl chloride (15.5. Mu.L, 0.22 mmol) was slowly added dropwise. The reaction was carried out at room temperature for 2h. The solution was quenched with saturated sodium bicarbonate solution, extracted with DCM (2 mL. Times.3), washed with saturated sodium chloride and dried over anhydrous sodium sulfate. Filtering, and concentrating the filtrate to obtain a crude product. Purification by silica gel column chromatography gave compound Zey-C1 (11 mg) in 25% yield and compound Zey-C2 (27 mg) in 71% yield.
Compound Zey-C1, white powder, 1 HNMR(500MHz,CDCl 3 )δδ8.01(dd,J＝8.2,1.1Hz,2H),7.99(d,J＝8.0,1.1Hz,2H),7.59-7.55(m,2H),7.44(t,J＝7.6Hz,4H),7.02(ddd,J＝10.3,3.6,0.9Hz,1H),6.38(dd,J＝10.3,1.1Hz,1H),5.95-5.93(m,1H),5.82(dd,J＝4.4,0.8Hz,1H),4.80(d,J＝11.4Hz,1H),4.71(d,J＝11.4Hz,1H),3.76(s,1H,OH),2.09(s,3H).
13 CNMR(125MHz,CDCl 3 )δ195.00(s),169.52(s),166.19(s),165.39(s),143.27(s),134.09(s),133.62(s),130.05(s),129.95(s),129.33(s),129.08(s),128.91(s),128.69(s),76.27(s),71.71(s),68.77(s),65.20(s),20.80(s).
HRMS(ESI):m/z calcd.C 243 H 20 NaO 8 [M+Na] + :447.1056,found 447.1056.
compound Zey-C2, white powder, 1 HNMR(500MHz,CDCl 3 )δ8.00(dd,J＝8.3,1.1Hz,2H),7.98(m,2H),7.57(dd,J＝6.8,2.4Hz,2H),7.45(dd,J＝7.7,2.3Hz,2H),6.87(dd,J＝10.5,2.1Hz,1H),6.32(dd,J＝10.5,2.3Hz,1H),6.18(d,J＝8.3Hz,1H),5.92(d,J＝8.3Hz,1H),4.89(d,J＝10.9Hz,1H),4.64(d,J＝11.0Hz,1H),2.18(s,3H),2.01(s,3H)
13 CNMR(125MHz,CDCl 3 )δ190.19(s),169.61(s),166.19(s),165.99(s),165.65(s),143.87(s),133.98(s),133.60(s),130.09(s),129.97(s),129.41(s),129.35(s),128.99(s),128.88(s),128.69(s),80.82(s),71.39(s),70.82(s),61.73(s),20.81(s),20.72(s).
HRMS(ESI):m/z calcd.C 25 H 22 NaO 9 [M+Na] + :489.1162,found 489.1158.
EXAMPLE 32 Synthesis of Compound Zey-C3 and Compound Zey-C4
According to the synthesis method of the compound Zey-C1 and the compound Zey-C2, propionyl chloride is used as a raw material to obtain a compound Zey-C3 (10 mg), and the yield is 24%. The compound Zey-C4 (30 mg) was obtained in 71% yield.
Zey-C3, white powder, 1 HNMR(600MHz,CDCl 3 )δ8.00(d,J＝7.3Hz,2H),7.96(d,J＝7.3Hz,2H),7.56(dd,J＝17.3,7.5Hz,2H),7.41(td,J＝7.8,3.7Hz,4H),7.00(dd,J＝10.2,3.7Hz,1H),6.37(d,J＝10.2Hz,1H),5.90(t,J＝3.9Hz,1H),5.81(d,J＝4.2Hz,1H),4.78(d,J＝11.4Hz,1H),4.67(d,J＝11.4Hz,1H),3.59(s,1H,OH),2.34(dd,J＝7.4,6.4Hz,2H),1.08(t,J＝7.5Hz,3H).
13 CNMR(150MHz,CDCl 3 )δ195.12(s),172.93(s),166.14(s),165.30(s),143.08(s),134.04(s),133.57(s),130.01(s),129.89(s),129.06(s),128.85(s),128.65(s),76.31(s),71.45(s),68.66(s),65.40(s),27.52(s),9.14(s).
HRMS(ESI):m/z calcd.C 24 H 22 NaO 8 [M+Na] + :461.1212,found 461.1156.
compound Zey-C4, white powder, 1 HNMR(600MHz,CDCl 3 )δ7.99(dd,J＝7.8,1.2Hz,2H),7.97(dd,J＝7.8,1.2Hz,2H),7.58-7.56(m,2H),7.44(m,4H),6.88(dd,J＝10.5,2.0Hz,1H),6.33(dd,J＝10.5,2.3Hz,1H),6.19(dd,J＝8.3,2.1Hz,1H),5.95(d,J＝8.4Hz,1H),4.88(d,J＝10.8Hz,1H),4.60(d,J＝10.9Hz,1H),2.46(q,J＝7.5Hz,2H),2.30-2.25(m,2H),1.17(t,J＝7.5Hz,3H),0.96(t,J＝7.5Hz,3H).
13 CNMR(150MHz,CDCl 3 )δ190.31(s),173.10(s),173.06(s),165.94(s),165.58(s),143.97(s),133.97(s),133.53(s),130.04(s),129.91(s),129.38(s),129.06(s),128.95(s),128.63(s),80.47(s),71.12(s),70.83(s),61.96(s),27.43(s),27.32(s),9.12(s),9.07(s)；
HRMS(ESI):m/z calcd.C 27 H 26 NaO 9 [M+Na] + :517.1475,found 517.1472。
EXAMPLE 33 Synthesis of Compound Zey-C5 and Compound Zey-C6
According to the synthesis method of the compound Zey-C1 and the compound Zey-C2, benzoyl chloride is used as a raw material to obtain the compound Zey-C5 (12 mg) with the yield of 20%. Zey-C6 (33 mg) was obtained in 64% yield.
Compound Zey-C5, white powder, 1 HNMR(600MHz,CDCl 3 )δ8.03(d,J＝7.3Hz,2H),7.98(d,J＝7.5Hz,4H),7.60-7.56(m,3H),7.45–7.40(m,6H),7.09(ddd,J＝10.3,3.4,1.8Hz,1H),6.49(d,J＝10.3Hz,1H),6.05(d,J＝3.7Hz,2H),4.93(d,J＝11.5Hz,1H),4.76(d,J＝11.5Hz,1H),3.79(s,1H,OH).
13 CNMR(125MHz,CDCl 3 )δ195.65(s),166.26(s),165.22(s),165.06(s),142.77(s),134.03(s),133.83(s),133.54(s),130.10(s),130.02(s),129.90(s),129.24(s),129.17(s),128.97(s),128.84(s),128.70(s),128.61(s),76.54(s),72.36(s),68.41(s),66.13(s).
HRMS(ESI):m/z calcd.C 28 H 22 NaO 8 [M+Na] + :509.1212,found 509.1208
compound Zey-C6, white powder, 1 HNMR(600MHz,CDCl 3 )δ8.09(dd,J＝8.3,1.2Hz,2H),7.97(dd,J＝8.3,1.2Hz,2H),7.89(ddd,J＝15.8,8.3,1.2Hz,4H),7.64(dd,J＝10.6,4.3Hz,1H),7.53-7.52(m,5H),7.37(dt,J＝24.6,7.9Hz,4H),7.29(d,J＝8.1Hz,2H),6.99(dd,J＝10.4,2.3Hz,1H),6.46(dd,J＝10.2,7.9Hz,2H),6.32(d,J＝8.1Hz,1H),5.05(d,J＝11.0Hz,1H),4.83(d,J＝11.0Hz,1H).
13 CNMR(125MHz,CDCl 3 )δ190.26(s),165.97(s),165.56(s),165.20(s),165.12(s),144.27(s),134.27(s),133.80(s),133.39(s),130.34(s),129.99(d,J＝17.8Hz),129.55(s),128.96(s),128.92(s),128.71(s),128.65(s),128.62(s),128.52(s),128.44(s),80.62(s),72.10(s),70.94(s),62.98(s).
HRMS(ESI):m/z calcd.C 35 H 26 NaO 9 [M+Na] + :613.1475,found 613.1470
EXAMPLE 34 Synthesis of Compound Zey-C7 and Compound Zey-C8
According to the synthesis method of the compound Zey-C1 and the compound Zey-C2, cinnamoyl chloride is used as a raw material to obtain the compound Zey-C7 (15 mg) with the yield of 18%. The compound Zey-C8 (37 mg) was obtained in 68% yield.
Compound Zey-C7, white powder, 1 HNMR(600MHz,CDCl 3 )δ8.03(dd,J＝7.3Hz,2H),8.01(dd,J＝7.3Hz,2H),7.71(d,J＝16.0Hz,1H),7.60-7.54(m,2H),7.50-7.49(m,2H),7.42(m,8H),7.07(dd,J＝10.3,3.7Hz,1H),6.45-6.42(d,J＝10.2Hz,1H),6.42(d,J＝16.0Hz,1H),6.04(dd,J＝5.7,2.2Hz,1H),5.96(d,J＝4.4Hz,1H),4.87(d,J＝11.4Hz,1H),4.76(d,J＝11.4Hz,1H),3.78(s,1H,OH).
13 CNMR(150MHz,CDCl 3 )δ195.07(s),166.11(s),165.25(d,J＝12.5Hz),146.88(s),143.08(s),133.90(d,J＝11.6Hz),133.40(s),130.77(s),129.89(s),129.80(s),128.94(s),128.93(s),128.70(s),128.70(s),128.48(s),128.34(s),128.14(s),116.43(s),76.24(s),71.80(s),68.58(s),65.50(s).
HRMS(ESI):m/z calcd.C 30 H 42 NaO 8 [M+Na] + :535.1369,found 535.1367
compound Zey-C8, white powder, 1 HNMR(600MHz,CDCl 3 )δ8.05-8.01(m,4H),7.83(d,J＝16.0Hz,1H),7.65(d,J＝16.0Hz,1H),7.60-7.58(m,3H),7.55(d,J＝7.4Hz,1H),7.46-7.41(m,10H),7.33(t,J＝7.3Hz,2H),6.97(dd,J＝10.5,2.1Hz,1H),6.58(d,J＝16.0Hz,1H),6.44-6.40(m,2H),6.39(d,J＝15.9Hz,2H),6.18(d,J＝8.3Hz,1H),5.03(d,J＝11.0Hz,1H),4.79(d,J＝11.0Hz,1H). 13 CNMR(150MHz,CDCl 3 )δ190.31(s),165.90(s),165.45(s),165.40(s),165.35(s),147.89(s),146.93(s),143.91(s),133.82(s),133.81(s),133.68(s),133.27(s),131.07(s),130.76(s),129.94(s),129.86(s),129.35(s),129.05(s),128.85(s),128.61(s),128.53(s),128.43(s),128.32(s),116.22(s),115.77(s),80.40(s),71.47(s),70.86(s),62.56(s)
HRMS(ESI):m/z calcd.C 39 H 22 NaO 9 [M+Na] + :665.1788,found 665.1795
the following are experimental test results of the xanthone derivatives of the present invention.
Testing of antitumor Activity of Zanthoxylum piperitum ketene derivatives (see Table 2)
The CCK8 method is adopted to perform activity tests on three cell lines of human malignant melanoma B16 cells, human liver cancer HepG2 cells and human neuroblastoma SH-SY5Y, and simultaneously perform activity tests on CIPP cells of the breast tumor of the dog.
The test results obtained were as follows: as shown in Table 2, most of the compounds have IC50 values within 10 μm/L and have good cytotoxic activity on tumor cells.
TABLE 2 Zanthoxylen ketene derivatives antitumor IC 50 Test results
Figure BDA0002781107230000251
Those of ordinary skill in the art will understand that: the discussion of any embodiment above is meant to be exemplary only, and is not intended to intimate that the scope of the disclosure, including the claims, is limited to these examples; the technical features of the above embodiments or different embodiments may also be combined within the inventive idea. Therefore, any omissions, modifications, substitutions, improvements and the like that may be made without departing from the spirit and principles of the invention are intended to be included within the scope of the invention.

Claims (11)

1. A sanshool ketene derivative is characterized in that: the zanthoxylum bungeanum ketene derivative is a first derivative of zanthoxylum bungeanum ketene with (-) -zeylenone configuration and a second derivative of zanthoxylum bungeanum ketene with (+) -zeylenone configuration;
the first derivative has a structure of formula (IV); the second derivative has a structure of formula (VI), formula (VIII), formula (IX) or formula (X);
Figure FDA0003721033450000011
wherein, in the formula (VIII), R is one of the following structures:
Figure FDA0003721033450000012
in formula (IX), R is one of the following structures:
Figure FDA0003721033450000013
in the formula (X), R 1 Is one of the following structures:
H
Figure FDA0003721033450000014
R 2 is one of the following structures:
Figure FDA0003721033450000021
and does not include R 1 Is H, R 2 Is composed of
Figure FDA0003721033450000022
2. The sanshool enone derivative according to claim 1, wherein the sanshool enone derivative having the structure of the formula (VIII) has any one of the following structures:
Figure FDA0003721033450000023
3. the sanshool ketene derivative according to claim 1, wherein the sanshool ketene derivative having the structure of formula (IX) has any one of the following structures:
Figure FDA0003721033450000024
4. the sanshool ketene derivative according to claim 1, wherein the sanshool ketene derivative having the structure of formula (X) has any one of the following structures:
Figure FDA0003721033450000031
5. a process for the preparation of the xanthone derivative of any of claims 1 to 4, comprising:
carrying out asymmetric dihydroxylation reaction on the first reactant and hydrogenated quinine 1,4- (2, 3-naphthyridine) diether in a mixed solvent of tetrahydrofuran and water to obtain a second reactant; carrying out cis-dihydroxy protection reaction on the second reactant, triphosgene and pyridine to obtain a third reactant; carrying out elimination reaction of carbonate ring on the third reactant in a mixed solvent of tetrahydrofuran and water; catalyzing the benzene reflux reaction; protecting a compound obtained by a catalytic benzene reflux reaction by cis-dihydroxy acetone acetal and subsequently protecting to obtain one of a compound with a structure shown in a formula (IV), a compound with a structure shown in a formula (IX), a compound with a structure shown in a formula (VIII) and a compound with a structure shown in a formula (X) respectively;
or
Reacting the second reactant with acetyl chloride under the catalysis of triethylamine and DMAP; reacting the obtained product with dichloromethane; reacting the obtained product with N, N-diisopropylethylamine and methylsulfonyl chloride to obtain a compound with a structure shown in a formula (VI);
wherein the first reactant is of formula (XI); the second reactant is of a structure shown in a formula (XII); the third reactant is of formula (XIII);
Figure FDA0003721033450000032
6. the process according to claim 5, wherein the compound of formula (IX) is prepared by:
carrying out cis-dihydroxy acetone acetal protection on a compound obtained by catalytic benzene reflux reaction, p-toluenesulfonic acid monohydrate and 2, 2-dimethoxypropane;
reacting the compound obtained by acetone acetal protection with dicyclohexylcarbodiimide and substituted benzene compounds under the catalysis of DMAP to obtain one of compounds with structures of formulas (IX-1) -formula (IX-4) and formula (IX-5) -formula (IX-6); wherein the structural formula of the compound of the formula (IX-5) is
Figure FDA0003721033450000041
Wherein, the substituted benzene compound is selected from one of benzoyl chloride and substituted benzene acid; the substituted benzoic acid is selected from one of p-fluorobenzoic acid, p-methoxybenzoic acid, p-methylbenzoic acid, cyclohexyl formic acid, phenylpropionic acid and phenylacetic acid; the mass ratio of the compound obtained through acetone acetal protection to DMAP, dicyclohexylcarbodiimide and substituted benzene acid is 10.
7. The method according to claim 6, wherein the method for preparing the compound having the structure of formula (VIII) specifically comprises:
dissolving one of the compounds with the structures of the formulas (IX-1) to (IX-2) and (IX-4) to (IX-6) in tetrahydrofuran, and carrying out hydrolysis reaction with diluted hydrochloric acid at room temperature to obtain the compound with the structure of the formula (VIII), wherein the molar ratio of the compounds with the structures of the formulas (IX-1) to (IX-2) and (IX-4) to (IX-6) to the diluted hydrochloric acid is 0.65.
8. The method according to claim 5, wherein the compound having the structure of formula (X) is prepared by:
reacting the sanshool (+) -zeylenone configuration with an acyl chloride compound under the catalysis of triethylamine and DMAP to obtain a compound with a structure shown in a formula (X); wherein the molar ratio of the acyl chloride compound to the sanshool (+) -zeylenone configuration is 2; the acyl chloride compound is one selected from acetyl chloride, propionyl chloride, benzoyl chloride and cinnamoyl chloride.
9. The preparation method according to claim 5, wherein the compound having the structure of formula (IV) is prepared by:
carrying out cis-dihydroxy acetone acetal protection on a compound obtained by catalytic benzene reflux reaction, p-toluenesulfonic acid monohydrate and 2, 2-dimethoxypropane; and reacting the compound obtained by the reaction with benzoyl chloride under the catalysis of triethylamine and DMAP to obtain the compound with the structure of the formula (IV).
10. Use of a sanshool ketene derivative according to any one of claims 1 to 4 or a sanshool ketene derivative prepared by the method for preparing the sanshool ketene derivative according to any one of claims 5 to 9 for preparing a therapeutic antitumor agent, wherein the tumor is at least one selected from the group consisting of malignant melanoma, human liver cancer, human neuroblastoma and canine breast tumor.
11. An antitumor agent comprising the sanshool derivative according to any one of claims 1 to 4 or the sanshool derivative produced by the method according to any one of claims 5 to 9 and a pharmaceutically acceptable excipient, wherein the antitumor agent is at least one selected from the group consisting of an antitumor agent against malignant melanoma, an antitumor agent against human liver cancer, an antitumor agent against human neuroblastoma and an antitumor agent against canine breast tumor.
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