CN113402483A - Pseudo-elemene diterpene derivative and preparation method and application thereof - Google Patents

Pseudo-elemene diterpene derivative and preparation method and application thereof Download PDF

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CN113402483A
CN113402483A CN202110670348.1A CN202110670348A CN113402483A CN 113402483 A CN113402483 A CN 113402483A CN 202110670348 A CN202110670348 A CN 202110670348A CN 113402483 A CN113402483 A CN 113402483A
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benzoyloxy
ethyl acetate
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阿吉艾克拜尔·艾萨
杨贺群
王边琳
汤丹
阿依提拉·麦麦提江
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Xinjiang Technical Institute of Physics and Chemistry of CAS
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Abstract

The invention relates to a pseudo-elenane diterpenoid derivative and a preparation method and application thereof. The derivatives are compounds 1-17 obtained by taking characteristic active ingredients ES3 contained in euphorbia pekinensis fruits as raw materials and adopting a plurality of derivatization methods, the method has mild reaction conditions and simple experimental steps, and preliminary multi-drug resistance reversal activity test is carried out on the synthesized compounds 1-17. Experimental results show that the compounds 1-17 show multidrug resistance reversal activities in different degrees, and can reverse the resistance of drug-resistant cells to antitumor drugs in different degrees when being used together with antitumor drugs, and the compounds 1, 2, 6,7, 8,9, 10, 11,12, 14, 15, 16 or 17 have stronger multidrug resistance reversal activities, and the reversal multiples of the compounds are all higher than that of a positive control drug verapamil. Among them, compound 12 exhibited the highest fold reversal. The compounds can be used as tumor multidrug resistance reversal medicines.

Description

Pseudo-elemene diterpene derivative and preparation method and application thereof
Technical Field
The invention relates to a pseudo-bruane diterpenoid derivative, a preparation method and application thereof, and application thereof in preparation of multidrug resistance reversal medicines or medicines combined with antitumor medicines.
Background
The structure of the pseudo-elenane diterpenoid compound is characterized in that the skeleton is formed by fusing a five-membered ring and a twelve-membered ring, namely 5/12 ring system. The compound has the characteristics of complex structure, high esterification degree, multiple substituent groups and large molecular weight. Because the positions, the number and the configuration of the substituents on the skeleton are different, the steric hindrance of the compounds is changed, and the structures of the compounds are completely different, so that the compounds have great influence on the multidrug resistance reversal activity of tumors. The diterpenoid compounds of the pseudoelemene type are characteristic active compounds of Euphorbia heterophylla (Euphorbia sororia), and the ES3 is a diterpenoid component with higher content, wherein the structure name of the ES3 is as follows: 14 beta-benzoyloxy-15 beta-hydroxy-5 alpha, 7 beta-diisobutyloxy-2 alpha, 3 beta, 8 alpha, 9 alpha-tetraacetoxy-pseudoolivine-6 (17), 11E-diene.
The tumor multidrug resistance refers to the phenomenon that after a drug acts on a tumor to generate drug resistance, the tumor has cross drug resistance to multiple antineoplastic drugs which are never contacted, have irrelevant structure, different targets and different mechanisms. One of the main action mechanisms is the overexpression of ABC family transporter (the P-gp protein coded by ABCB1 gene which is the most widely and deeply researched at present) so as to increase the drug efflux and form drug resistance. The search for modulators from natural products and derivatives thereof that are capable of targeting ABC transporter proteins has become one of the most promising approaches for global lead compound development. Macrocyclic diterpenes, characteristic components of euphorbia plants, are of great interest because of their good targeting properties and outstanding multidrug resistance reversal activity.
Therefore, the structural formula ES3 is used as a raw material, a series of derivatives are synthesized with high yield by a plurality of synthesis methods, the selectivity is good, the reaction condition is mild, and the experimental steps are simple. The aim of reversing drug resistance of drug-resistant cells is achieved by investigating the combined use of the novel compound and the traditional anti-tumor drug and utilizing competitive combination of transport proteins on drug-resistant cell membranes as substrates, so that the traditional anti-tumor drug can play a role in killing tumor cells in cells, and the multi-drug resistance reversing activity of the novel compound is evaluated.
Disclosure of Invention
The invention aims to provide a pseudo-elemene diterpenoid derivative, a preparation method and application thereof, wherein the derivative takes an active ingredient ES3 in euphorbia pekinensis as a raw material, and compounds 1-17 are obtained under different conditions. And the synthesized compounds 1-17 are subjected to preliminary tumor multidrug resistance reversal activity tests, and experimental results show that IC (integrated Circuit) is compared with the single action of adriamycin after adriamycin is respectively combined with the compounds 1, 2, 6,7, 8,9, 10, 11,12, 14, 15, 16 and 1750The value is significantly reduced; under the same concentration (10 mu M), the compounds 1, 10, 11,12, 14, 15, 16 and 17 have stronger multidrug resistance reversal activity, the reversal times of the compounds are all higher than that of a positive control drug verapamil, and in addition, the compounds 2, 6,7, 8 and 9 have certain multidrug resistance reversal activity when being combined with an antitumor drug adriamycin. The compounds can be used as multidrug resistance reversal medicines.
The invention relates to a pseudo-elenane diterpenoid derivative, which has the structural formula as follows:
Figure BDA0003118961380000021
Figure BDA0003118961380000031
wherein:
the name of structural formula 1 is: (2R,3R,4S,5R,7S,8S,9S,11S,12S,13S,14S,15R) -14-benzoyloxy-15-hydroxy-11, 12-epoxy-5, 7-diisobutyloxy-2, 3,8, 9-tetraacetoxy-pseudooliv-ine-6 (17) -ene;
the name of structural formula 2 is: (2R,3R,5S,7S,8S,9S,13S,14S) -14-benzoyloxy-5, 7-diisobutyloxy-2, 3,8, 9-tetraacetoxy-pseudoolivine-6 (17),4E, 11E-triene;
the name of structural formula 3 is: 14 β -benzoyloxy-2 α,7 β,8 α,9 α,15 β -pentahydroxy-5 α -isobutyryloxy-3 β -acetoxy-pseudoolivine-6 (17), 11E-diene;
the name of structural formula 4 is: 14 β -benzoyloxy-2 α,9 α,15 β -trihydroxy-5 α -isobutyryloxy-3 β,7 β,8 α -triacetoxy-pseudoolivine-6 (17), 11E-diene;
the name of structural formula 5 is: 14 beta-benzoyloxy-2 alpha, 8 alpha, 9 alpha, 15 beta, 17-pentahydroxy-5 alpha-isobutyryloxy-3 beta-triacetoxy-6, 7 epoxy-pseudoelemene-11E-ene;
the name of structural formula 6 is: 14 β -benzoyloxy-2 α,7 β,9 α,15 β -tetrahydroxy-5 α -isobutyryloxy-3 β -acetoxy-8 α -3' -methyl-benzoyloxy-pseudoolivine-6 (17), 11E-diene;
the name of structural formula 7 is: 14 β -benzoyloxy-2 α,8 α,9 α,15 β -tetrahydroxy-5 α -isobutyryloxy-3 β -acetoxy-7 β -3' -methylbenzoyloxy-pseudoolivine-6 (17), 11E-diene;
the name of structural formula 8 is: 14 β -benzoyloxy-2 α,15 β -dihydroxy-5 α -isobutyryloxy-3 β,7 β,8 α,9 α -tetraacetoxy-pseudoolivine-6 (17), 11E-diene;
the name of structural formula 9 is: 14 β -benzoyloxy-15 β -hydroxy-5 α -isobutyryloxy-2 α,3 β,7 β,8 α,9 α -pentaacetoxy-pseudoolivine-6 (17), 11E-diene;
the name of structural formula 10 is: 14 β -benzoyloxy-15 β -hydroxy-5 α -isobutyryloxy-3 β,7 β,8 α,9 α -tetraacetoxy-2 α -3' -methyl-benzoyloxy-pseudoolivine-6 (17), 11E-diene;
the name of structural formula 11 is: 14 β -benzoyloxy-15 β -hydroxy-5 α -isobutyryloxy-3 β,7 β,8 α,9 α -tetraacetoxy-2 α -isonicotinyloxy-pseudoCanane-6 (17), 11E-diene;
the name of structural formula 12 is: 14 β -benzoyloxy-15 β -hydroxy-5 α -isobutyryloxy-3 β,7 β,8 α,9 α -tetraacetoxy-2 α -pivaloyloxy-pseudoolivine-6 (17), 11E-diene;
the name of structural formula 13 is: 14 β -benzoyloxy-2 α,7 β,9 α,15 β -tetrahydroxy-5 α -isobutyryloxy-3 β -acetoxy-8 α -pivaloyloxy-pseudoolivine-6 (17), 11E-diene;
the name of structural formula 14 is: 14 β -benzoyloxy-2 α,15 β -dihydroxy-5 α -isobutyryloxy-3 β,7 β,9 α -triacetoxy-8 α -3' -methyl-benzoyloxy-pseudoolivine-6 (17), 11E-diene;
the name of structural formula 15 is: 14 β -benzoyloxy-15 β -hydroxy-5 α -isobutyryloxy-2 α,3 β,7 β,9 α -tetraacetoxy-8 α -3' -methyl-benzoyloxy-pseudoolivine-6 (17), 11E-diene;
the name of structural formula 16 is: 14 β -benzoyloxy-2 α,15 β -dihydroxy-5 α -isobutyryloxy-3 β,7 β,9 α -triacetoxy-8 α -pivaloyloxy-pseudoolivine-6 (17), 11E-diene;
the name of structural formula 17 is: 14 beta-benzoyloxy-15 beta-hydroxy-5 alpha-isobutyryloxy-2 alpha, 3 beta, 7 beta, 9 alpha-tetraacetoxy-8 alpha-pivaloyloxy-pseudoolivine-6 (17), 11E-diene.
The preparation method of the pseudo-elemene diterpene derivative takes an active ingredient structural formula ES3 in a plant euphorbia pekinensis as a raw material, and the specific operation is carried out according to the following steps:
a. dissolving a compound 14 beta-benzoyloxy-15 beta-hydroxy-5 alpha, 7 beta-diisobutyloxy-2 alpha, 3 beta, 8 alpha, 9 alpha-tetraacetoxy-pseudoleucomelane-6 (17), 11E-diene in dichloromethane, adding 2 times of m-chloroperoxybenzoic acid, stirring at room temperature for 6 days, quenching saturated sodium thiosulfate, extracting with ethyl acetate, washing with saturated sodium bicarbonate, water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating ethyl acetate, performing silica gel column 200-mesh gradient elution with 300 meshes, eluting with petroleum ether and ethyl acetate in a volume ratio of 3:1 to obtain a white solid compound 1 of (2R,3R,4S,5R,7S,8S,9S,11S,12S,13S,14S,15R) -14-benzoyloxy-15-hydroxy-11, 12-epoxy-5, 7-diisobutyloxy-2, 3,8, 9-tetraacetoxy-pseudoolivine-6 (17) -ene;
or dissolving a compound 14 beta-benzoyloxy-15 beta-hydroxy-5 alpha, 7 beta-diisobutyloxy-2 alpha, 3 beta, 8 alpha, 9 alpha-tetraacetoxy-pseudo-white-elenane-6 (17), 11E-diene in toluene, adding 10 times of thionyl chloride, protecting nitrogen, heating to 70 ℃, stirring for reaction for 1 hour, adding saturated sodium bicarbonate for quenching, extracting ethyl acetate, washing with water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating the ethyl acetate, performing gradient elution with a silica gel column of 200 meshes and 300 meshes, wherein the eluent is petroleum ether and ethyl acetate with the volume ratio of 5:1, and the white solid compound 2 is (2R,3R,5S,7S,8S,9S,13S,14S) -14-benzoyloxy-5, 7-diisobutyloxy-2, 3,8, 9-tetraacetoxy-pseudoolivine-6 (17),4E, 11E-triene;
or dissolving a compound 14 beta-benzoyloxy-15 beta-hydroxy-5 alpha, 7 beta-diisobutyloxy-2 alpha, 3 beta, 8 alpha, 9 alpha-tetraacetoxy-pseudoCanane-6 (17), 11E-diene in methanol, adding 2 times of 1, 8-diazabicycloundecene-7-ene, stirring for 2.5 hours at room temperature, adding hydrochloric acid (1mmol/L) for quenching, extracting with ethyl acetate, washing with water, saturated sodium bicarbonate and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating ethyl acetate, performing gradient elution with a silica gel column of 200 meshes and 300 meshes, eluting with petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain a white solid compound 3 of 14 beta-benzoyloxy-2 alpha, 7 beta, 8 alpha and 9 alpha, 15 β -pentahydroxy-5 α -isobutyryloxy-3 β -acetoxy-pseudoolivine-6 (17), 11E-diene;
b. dissolving the compound 3 obtained in the step a, namely 14 beta-benzoyloxy-2 alpha, 7 beta, 8 alpha, 9 alpha, 15 beta-pentahydroxyl-5 alpha-isobutyryloxy-3 beta-acetoxyl-pseudo-white-elenane-6 (17), 11E-diene, in dichloromethane, adding triethylamine and 3 times of acetic anhydride, stirring at room temperature for 8-12 hours, adding saturated sodium bicarbonate for quenching, extracting with ethyl acetate, washing with water, saturated sodium bicarbonate and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating ethyl acetate, performing gradient elution with a silica gel column of 200 meshes to 300 meshes, wherein an eluent is petroleum ether and ethyl acetate with the volume ratio of 1.5:1, and obtaining a white solid compound 4, namely 14 beta-benzoyloxy-2 alpha, 9 alpha, 15 beta-trihydroxy-5 alpha-isobutyryloxy-3 beta, 7 β,8 α -triacetoxy-pseudoolivine-6 (17), 11E-diene;
or dissolving the compound 3 obtained in the step a into 14 beta-benzoyloxy-2 alpha, 7 beta, 8 alpha, 9 alpha, 15 beta-pentahydroxy-5 alpha-isobutyryloxy-3 beta-acetoxyl-pseudo-white-elenane-6 (17), 11E-diene into dichloromethane, adding 1.5 times of m-chloroperoxybenzoic acid, stirring at room temperature for 24 hours, quenching with saturated sodium thiosulfate, extracting with ethyl acetate, washing with saturated sodium bicarbonate, water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating ethyl acetate, performing gradient elution with a silica gel column of 200 meshes to 300 meshes, eluting with petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain a white solid compound 5, namely 14 beta-benzoyloxy-2 alpha, 8 alpha, 9 alpha, 15 beta, 17-pentahydroxy-5 alpha-isobutyryloxy-3 beta-triacetoxy-6, 7 epoxy-pseudoolivine-11E-ene;
or dissolving the compound 314 beta-benzoyloxy-2 alpha, 7 beta, 8 alpha, 9 alpha, 15 beta-pentahydroxy-5 alpha-isobutyryloxy-3 beta-acetoxyl-pseudo-white olive-6 (17), 11E-diene obtained in the step a in pyridine, adding 2 times of 3-methylbenzoyl chloride, stirring at room temperature for 1 hour, adding saturated sodium bicarbonate to quench, extracting with ethyl acetate, washing with water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating the ethyl acetate, performing 200-mesh gradient elution through a silica gel column with 300 meshes, and eluting with petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain a white solid compound 6 of 14 beta-benzoyloxy-2 alpha, 7 beta, 9 alpha, 15 beta-tetrahydroxy-5 alpha-isobutyryloxy-3 beta-acetoxyl-8 alpha-3' -methyl-ethyl propionate Benzoyloxy-pseudoolivine-6 (17), 11E-diene;
or dissolving the compound 3 obtained in the step a, namely 14 beta-benzoyloxy-2 alpha, 7 beta, 8 alpha, 9 alpha, 15 beta-pentahydroxy-5 alpha-isobutyryloxy-3 beta-acetoxyl-pseudo-white-elenane-6 (17), 11E-diene, in dichloromethane, adding triethylamine, 5 times of acetic anhydride and a catalytic amount of 4-dimethylaminopyridine, stirring for 2 hours at room temperature, adding saturated sodium bicarbonate for quenching, extracting ethyl acetate, washing with water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating ethyl acetate, performing gradient elution with a silica gel column of 200 meshes and 300 meshes, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 1:1, and obtaining a white solid compound 8, namely 14 beta-benzoyloxy-2 alpha, 15 beta-dihydroxy-5 alpha-isobutyryloxy-3 beta, 7 β,8 α,9 α -tetraacetoxy-pseudoolivine-6 (17), 11E-diene;
or dissolving the compound 3 obtained in the step a, namely 14 beta-benzoyloxy-2 alpha, 7 beta, 8 alpha, 9 alpha, 15 beta-pentahydroxy-5 alpha-isobutyryloxy-3 beta-acetoxyl-pseudo-brumelane-6 (17), 11E-diene, into pyridine, adding 2 times of pivaloyl chloride, stirring at room temperature for 2 hours, adding saturated sodium bicarbonate for quenching, extracting ethyl acetate, washing with water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating the ethyl acetate, performing 200-mesh gradient elution through a silica gel column with 300 meshes, and eluting with petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain a white solid compound 13, namely 14 beta-benzoyloxy-2 alpha, 7 beta, 9 alpha, 15 beta-tetrahydroxy-5 alpha-isobutyryloxy-3 beta-acetoxyl-8 alpha-pivaloyloxy-pseudo-bruamane- 6, (17), 11E-diene;
c. standing the compound 6 obtained in the step b in methanol water solution for 7 days to obtain a white solid compound 714 beta-benzoyloxy-2 alpha, 8 alpha, 9 alpha, 15 beta-tetrahydroxy-5 alpha, 7 beta, 9 alpha, 15 beta-tetrahydroxy-5 alpha-isobutyryloxy-3 beta-acetoxy-8 alpha-3 '-methyl-benzoyloxy-pseudo-white olive-6 (17), concentrating, performing gradient elution through a silica gel column with 200 meshes and 300 meshes, and eluting with petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain a white solid compound 714 beta-benzoyloxy-2 alpha, 8 alpha, 9 alpha, 15 beta-tetrahydroxy-5 alpha-isobutyryloxy-3 beta-acetoxy-7 beta-3' -methylbenzoyloxy-pseudo-white olive-6 (17), 11E-diene;
or dissolving the compound 6 obtained in the step b into 14 beta-benzoyloxy-2 alpha, 7 beta, 9 alpha, 15 beta-tetrahydroxy-5 alpha-isobutyryloxy-3 beta-acetoxyl-8 alpha-3' -methyl-benzoyloxy-pseudo-white-elenane-6 (17), 11E-diene in dichloromethane, adding triethylamine, 5 times of acetic anhydride and a catalytic amount of 4-dimethylaminopyridine, stirring for 2 hours at room temperature, adding saturated sodium bicarbonate to quench, extracting with ethyl acetate, washing with water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating the ethyl acetate, performing gradient elution through a silica gel column with 200 meshes and 300 meshes, eluting with petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain a white solid compound 14 of 14 beta-benzoyloxy-2 alpha, 15 β -dihydroxy-5 α -isobutyryloxy-3 β,7 β,9 α -triacetoxy-8 α -3' -methyl-benzoyloxy-pseudoolivine-6 (17), 11E-diene;
or dissolving the compound 8 obtained in the step b into pyridine, adding 5 times of acetic anhydride and catalytic amount of 4-dimethylamino pyridine, refluxing and stirring for 24 hours, adding saturated sodium bicarbonate for quenching, extracting ethyl acetate, washing with water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating the ethyl acetate, performing gradient elution through a silica gel column with 200 meshes and 300 meshes, and eluting with petroleum ether and ethyl acetate in a volume ratio of 2:1 to obtain a white solid compound 9 of 14 beta-benzoyloxy-15 beta-hydroxy-5 alpha-isobutyryloxy-2 alpha, 3 β,7 β,8 α,9 α -pentaacetoxy-pseudoolivine-6 (17), 11E-diene;
or dissolving the compound 8 obtained in the step b into pyridine, adding 3-methyl benzoyl chloride in an amount which is 3 times that of the 14 beta-benzoyloxy-2 alpha, 15 beta-dihydroxy-5 alpha-isobutyryloxy-3 beta, 7 beta, 8 alpha, 9 alpha-tetraacetoxy-pseudoCanane-6 (17), 11E-diene, refluxing and stirring for 24 hours, adding saturated sodium bicarbonate for quenching, extracting with ethyl acetate, washing with water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating the ethyl acetate, performing gradient elution with a silica gel column of 200 meshes and 300 meshes, and eluting with petroleum ether and ethyl acetate in a volume ratio of 2:1 to obtain a white solid compound 10 of 14 beta-benzoyloxy-15 beta-hydroxy-5 alpha-isobutyryloxy-3 beta, 7 β,8 α,9 α -tetraacetoxy-2 α -3' -methyl-benzoyloxy-pseudoolivine-6 (17), 11E-diene;
or dissolving the compound 8 obtained in the step b into pyridine, adding 3 times of isonicotinoyl chloride and catalytic amount of 4-dimethylamino pyridine, refluxing and stirring for 4 hours, adding saturated sodium bicarbonate for quenching, extracting ethyl acetate, washing with water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating the ethyl acetate, performing gradient elution with a silica gel column of 200 meshes to 300 meshes, and eluting with petroleum ether and ethyl acetate in a volume ratio of 2:1 to obtain a white solid compound 11 of 14 beta-benzoyloxy-15 beta-hydroxy-5 alpha-isobutyryloxy-3 beta, 7 β,8 α,9 α -tetraacetoxy-2 α -isonicotinyloxy-pseudoCanane-6 (17), 11E-diene;
or dissolving the compound 8 obtained in the step b into pyridine, adding 2 times of pivaloyl chloride and 4-dimethylamino pyridine with pivaloyl chloride amount, refluxing and stirring for 18 hours, adding saturated sodium bicarbonate to quench, extracting with ethyl acetate, washing with water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating the ethyl acetate, performing gradient elution with a silica gel column of 200 meshes and 300 meshes, and eluting with petroleum ether and ethyl acetate in a volume ratio of 3:1 to obtain a white solid compound 12 of 14 beta-benzoyloxy-15 beta-hydroxy-5 alpha-isobutyryloxy-3 beta, 7 β,8 α,9 α -tetraacetoxy-2 α -pivaloyloxy-pseudoCanane-6 (17), 11E-diene;
d. dissolving the compound 13 obtained in the step b into 14 beta-benzoyloxy-2 alpha, 7 beta, 9 alpha, 15 beta-tetrahydroxy-5 alpha-isobutyryloxy-3 beta-acetoxyl-8 alpha-pivaloyloxy-pseudowhite elenane-6 (17), 11E-diene into dichloromethane, adding triethylamine, 4 times of acetic anhydride and catalytic amount of 4-dimethylaminopyridine, stirring for 2 hours at room temperature, adding saturated sodium bicarbonate for quenching, extracting with ethyl acetate, washing with water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating the ethyl acetate, performing gradient elution with a silica gel column of 200 meshes and 300 meshes, and eluting with petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain a white solid compound 16 of 14 beta-benzoyloxy-2 alpha, 15 β -dihydroxy-5 α -isobutyryloxy-3 β,7 β,9 α -triacetoxy-8 α -pivaloyloxy-pseudoolivine-6 (17), 11E-diene;
e. dissolving the compound 14 obtained in the step c into pyridine, adding 5 times of acetic anhydride and catalytic amount of 4-dimethylamino pyridine, refluxing and stirring for 48 hours, adding saturated sodium bicarbonate to quench, extracting with ethyl acetate, washing with water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating the ethyl acetate, performing 200-mesh and 300-mesh gradient elution through a silica gel column, and eluting with petroleum ether and ethyl acetate in a volume ratio of 2:1 to obtain a white solid compound 15, namely 14 beta-benzoyloxy-15 beta-hydroxy-5 alpha-isobutyryloxy-2 alpha, 3 β,7 β,9 α -tetraacetoxy-8 α -3' -methyl-benzoyloxy-pseudoolivine-6 (17), 11E-diene;
f. dissolving the compound 16 obtained in the step d into 14 beta-benzoyloxy-2 alpha, 15 beta-dihydroxy-5 alpha-isobutyryloxy-3 beta, 7 beta, 9 alpha-triacetoxy-8 alpha-pivaloyloxy-pseudoCanane-6 (17), 11E-diene, adding 3 times of acetic anhydride and catalytic amount of 4-dimethylaminopyridine, refluxing and stirring for 48 hours, adding saturated sodium bicarbonate for quenching, extracting with ethyl acetate, washing with water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating the ethyl acetate, performing gradient elution with a silica gel column of 200 meshes and 300 meshes, and eluting with petroleum ether and ethyl acetate in a volume ratio of 2:1 to obtain a white solid compound 17 of 14 beta-benzoyloxy-15 beta-hydroxy-5 alpha-isobutyryloxy-2 alpha, 3 β,7 β,9 α -tetraacetoxy-8 α -pivaloyloxy-pseudoCanane-6 (17), 11E-diene.
The application of the compound 1, 2, 6,7, 8,9, 10, 11,12, 14, 15, 16 or 17 in the preparation of the drug with multidrug resistance reversal activity is provided.
The invention relates to a pseudo-elenane diterpenoid derivative, a preparation method and application thereof, wherein the derivative takes an active ingredient structural formula ES3 in a plant euphorbia pekinensis as a raw material, and the structural formula is as follows:
Figure BDA0003118961380000071
the structure name of ES3 is: 14 beta-benzoyloxy-15 beta-hydroxy-5 alpha, 7 beta-diisobutyloxy-2 alpha, 3 beta, 8 alpha, 9 alpha-tetraacetoxy-pseudoolivine-6 (17), 11E-diene.
The invention relates to a pseudo-elemene diterpenoid derivative, a preparation method and an application thereof, and the preparation method has the following beneficial effects: the derivatives take ES3 as raw materials, react under different conditions, selectively obtain a plurality of derivatives, have high yield, simple operation and mild reaction conditions, and are used for industrial production. Has important theoretical and application value for researching the relationship between the biological activity and the summary structure activity of the compound.
Detailed Description
The present invention is further illustrated by the following examples, but the present invention is not limited to these examples.
Example 1
Preparation of compound 1 name: (2R,3R,4S,5R,7S,8S,9S,11S,12S,13S,14S,15R) -14-benzoyloxy-15-hydroxy-11, 12-epoxy-5, 7-diisobutyloxy-2, 3,8, 9-tetraacetoxy-pseudooliv-ine-6 (17) -ene:
dissolving ES3 (14 beta-benzoyloxy-15 beta-hydroxy-5 alpha, 7 beta-diisobutyloxy-2 alpha, 3 beta, 8 alpha, 9 alpha-tetraacetoxy-pseudoolivine-6 (17)), 11E-diene 81mg,0.10mmol in dichloromethane 2mL, adding 41mg,0.20mmol, 85% of m-chloroperoxybenzoic acid, stirring at room temperature for 6 days, quenching with saturated sodium thiosulfate, extracting with ethyl acetate, washing with saturated sodium bicarbonate, water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating organic phase ethyl acetate, gradient eluting with silica gel column 200-300 meshes, eluting with petroleum ether and ethyl acetate at volume ratio of 3:1 to obtain white solid compound 1, wherein: (2R,3R,4S,5R,7S,8S,9S,11S,12S,13S,14S,15R) -14-benzoyloxy-15-hydroxy-11, 12-epoxy-5, 7-diisobutyloxy-2, 3,8, 9-tetraacetoxy-pseudoelemene-6 (17) -ene 40mg, yield 48%;
mass spectra and nuclear magnetic data were: ESI (+) MS M/z 853.3832[ M + Na ]]+Molecular formula is C43H58O16.1H NMR(400MHz,CDCl3)δppm:3.68(1H,d,J＝16.5Hz,H-1α),2.18(1H,d,J＝16.5Hz,H-1β),5.31(1H,d,J＝3.2Hz,H-3),2.94(1H,dd,J＝11.0,3.3Hz,H-4),6.15(1H,d,J＝11.0Hz,H-5),5.36(1H,d,J＝6.7Hz,H-7),5.60(1H,d,J＝5.6Hz,H-8),5.24(1H,d,J＝7.7Hz,H-9),3.02(1H,d,J＝1.8Hz,H-11),3.25(1H,dd,J＝7.9,1.9Hz,H-12),1.47(1H,m,H-13),5.59(1H,br s,H-14),1.53(3H,s,H3-16),5.61(1H,s,H-17α),5.54(1H,s,H-17β),1.03(3H,s,H3-18),0.57(3H,s,H3-19),1.24(3H,d,J＝7.2Hz,H3-20),15-OH:3.98(1H,s)；2-OAc:2.38(3H,s)；3-OAc:2.23(3H,s)；8-OAc:1.67(3H,s)；9-OAc:2.03(3H,s)；5-OiBu:2.30(1H,m,H-2'),1.02(3H,d,J＝7.0Hz,H-3'),1.00(3H,d,J＝7.0Hz,H-4')；7-OiBu:2.40(1H,m,H-2'),1.02(3H,d,J＝6.9Hz,H-3'),1.12(3H,d,J＝7.1Hz,H-4')；14-OBz:7.97(2H,d,J＝7.7Hz,H-3',7'),7.43(2H,t,J＝7.7Hz,H-4',6'),7.56(1H,t,J＝7.6Hz,H-5').13C NMR(100MHz,CDCl3)δppm:50.6(C-1),86.9(C-2),79.9(C-3),50.9(C-4),66.0(C-5),141.9(C-6),72.9(C-7),68.9(C-8),78.8(C-9),39.0(C-10),60.3(C-11),59.6(C-12),43.2(C-13),74.9(C-14),82.5(C-15),19.8(C-16),125.6(C-17),25.3(C-18),16.4(C-19),13.7(C-20),2-OAc:169.8(CO),21.3(C-2')；3-OAc:169.9(CO),21.3(C-2')；8-OAc:170.1(CO),22.7(C-2')；9-OAc:169.9(CO),21.4(C-2')；5-OiBu:173.9(CO),34.1(C-2'),18.6(C-3'),18.8(C-4')；7-OiBu:176.0(CO),33.8(C-2'),19.0(C-3'),19.3(C-4')；14-OBz:165.1(CO),130.2(C-2'),129.7(C-3',7'),128.8(C-4',6'),133.6(C-5')。
Example 2
Preparation of compound 2 name: (2R,3R,5S,7S,8S,9S,13S,14S) -14-benzoyloxy-5, 7-diisobutyloxy-2, 3,8, 9-tetraacetoxy-pseudoolivine-6 (17),4E, 11E-triene:
dissolving ES3 (14 beta-benzoyloxy-15 beta-hydroxy-5 alpha, 7 beta-diisobutyloxy-2 alpha, 3 beta, 8 alpha, 9 alpha-tetraacetoxy-pseudoolivine-6 (17)), 11E-diene 46mg and 0.056mmol in toluene 3mL, adding thionyl chloride 0.1mL, heating to 70 ℃ under nitrogen protection, stirring for reaction for 1 hour, adding saturated sodium bicarbonate for quenching, extracting ethyl acetate, washing with water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating organic phase ethyl acetate, performing gradient elution through a silica gel column with 200 meshes and 300 meshes, and eluting with petroleum ether and ethyl acetate in a volume ratio of 5:1 to obtain colorless crystals 2: (2R,3R,5S,7S,8S,9S,13S,14S) -14-benzoyloxy-5, 7-diisobutyloxy-2, 3,8, 9-tetraacetoxy-pseudoolivine-6 (17),4E, 11E-triene 40mg, yield 89%;
mass spectra and nuclear magnetic data were: ESI (+) MS M/z 819.3570[ M + Na ]]+Molecular formula is C43H56O14.1H NMR(400MHz,CDCl3)δppm:3.13(1H,d,J＝16.8Hz,H-1α),3.00(1H,d,J＝16.8Hz,H-1β),5.76(1H,s,H-3),5.23(1H,br s,H-5),5.81(1H,s,H-7),5.24(1H,s,H-8),5.04(1H,s,H-9),5.91(1H,s,H-11),5.91(1H,s,H-12),2.71(1H,m,H-13),5.96(1H,br s,H-14),1.45(3H,s,H3-16),5.08(1H,s,H-17α),4.73(1H,s,H-17β),0.95(3H,s,H3-18),1.45(3H,s,H3-19),1.14(3H,d,J＝7.0Hz,H3-20)；2-OAc:2.03(3H,s)；3-OAc:1.94(3H,s)；8-OAc:2.00(3H,s)；9-OAc:2.00(3H,s)；5-OiBu:1.63(1H,m,H-2'),0.54(3H,d,J＝7.0Hz,H-3'),0.69(3H,d,J＝7.1Hz,H-4')；7-OiBu:2.57(1H,m,H-2'),1.18(3H,d,J＝7.0Hz,H-3'),1.22(3H,d,J＝7.1Hz,H-4')；14-OBz:7.99(2H,d,J＝7.6Hz,H-3',7'),7.43(2H,t,J＝7.6Hz,H-4',6'),7.53(1H,t,J＝7.5Hz,H-5').13C NMR(100MHz,CDCl3)δppm:48.2(C-1),88.0(C-2),84.5(C-3),147.6(C-4),78.4(C-5),144.6(C-6),67.0(C-7),71.4(C-8),80.0(C-9),40.4(C-10),136.7(C-11),129.2(C-12),40.6(C-13),67.7(C-14),147.6(C-15),20.0(C-16),111.2(C-17),26.6(C-18),24.3(C-19),22.1(C-20)；2-OAc:170.8(CO),22.3(C-2')；3-OAc:169.4(CO),21.1(C-2')；8-OAc:170.1(CO),21.0(C-2')；9-OAc:170.0(CO),20.9(C-2')；5-OiBu:174.1(CO),33.7(C-2'),18.3(C-3'),18.6(C-4')；7-OiBu:175.4(CO),34.2(C-2'),18.7(C-3'),19.3(C-4')；14-OBz:165.8(CO),128.1(C-2'),130.2(C-3',7'),128.9(C-4',6'),133.5(C-5')。
Example 3
Preparation of compound 3 name: 14 beta-benzoyloxy-2 alpha, 7 beta, 8 alpha, 9 alpha, 15 beta-pentahydroxy-5 alpha-isobutyryloxy-3 beta-acetoxy-pseudoolivine-6 (17), 11E-diene
Dissolving ES3 14 beta-benzoyloxy-15 beta-hydroxy-5 alpha, 7 beta-diisobutyloxy-2 alpha, 3 beta, 8 alpha, 9 alpha-tetraacetoxy-pseudoolivine-6 (17), 11E-diene 842mg,1.03mmol in methanol 10mL, adding 1, 8-diazabicycloundecene 318mg,2.09mmol, stirring for 3.5 hours at room temperature, adding hydrochloric acid 1mmol/L,3mL to quench, extracting with ethyl acetate for 3 times, washing with water, saturated sodium bicarbonate, saturated sodium chloride, drying with sodium sulfate, concentrating organic phase ethyl acetate, gradient eluting with silica gel column 200-300 mesh, eluting with petroleum ether and ethyl acetate at volume ratio of 1:2 to obtain white solid compound 3 named as 14 beta-benzoyloxy-2 alpha, 7 beta, 8 alpha, 9 alpha, 15 beta-pentahydroxy-5 alpha-isobutyryloxy-3 beta-acetoxy-pseudo-elenane-6 (17), 11E-diene 400mg, yield 63%;
mass spectra and nuclear magnetic data were: ESI (+) MS M/z 641.2943[ M + Na ]]+Molecular formula is C33H46O11.1H NMR(400MHz,CDCl3)δppm:2.15(1H,d,J＝14.8Hz,H-1α),2.07(1H,d,J＝14.8Hz,H-1β),5.10(1H,d,J＝4.6Hz,H-3),3.03(1H,m,H-4),5.68(1H,d,J＝2.9Hz,H-5),4.38(1H,s,H-7),4.08(1H,s,H-8),3.74(1H,s,H-9),5.86(1H,d,J＝16.0Hz,H-11),5.70(1H,dd,J＝16.0,6.2Hz,H-12),2.77(1H,m,H-13),5.35(1H,s,H-14),1.31(3H,s,H3-16),5.13(1H,s,H-17α),4.64(1H,s,H-17β),1.08(3H,s,H3-18),1.22(3H,s,H3-19),1.07(3H,d,J＝6.2Hz,H3-20),2-OH:3.47(1H,s)；7-OH:4.08(1H,s)；8-OH:4.08(1H,s)；9-OH:4.09(1H,s)；15-OH:4.09(1H,s)；3-OAc:2.05(3H,s)；5-OiBu:2.09(1H,m,H-2'),0.67(3H,d,J＝7.0Hz,H-3'),0.82(3H,d,J＝7.0Hz,H-4')；14-OBz:7.95(2H,d,J＝7.5Hz,H-3',7'),7.43(2H,t,J＝7.7Hz,H-4',6'),7.53(1H,t,J＝7.4Hz,H-5').13C NMR(100MHz,CDCl3)δppm:54.3(C-1),84.0(C-2),84.1(C-3),44.1(C-4),72.5(C-5),148.0(C-6),67.6(C-7),70.7(C-8),84.7(C-9),40.5(C-10),134.9(C-11),130.1(C-12),37.7(C-13),79.5(C-14),78.5(C-15),24.6(C-16),107.5(C-17),27.6(C-18),14.0(C-19),23.8(C-20),3-OAc:171.4(CO),21.5(C-2')；5-OiBu:174.9(CO),34.1(C-2'),18.2(C-3'),18.4(C-4')；14-OBz:166.4(CO),129.8(C-2'),130.0(C-3',7'),128.8(C-4',6'),133.3(C-5')。
Example 4
Preparation of compound 4 name: 14 β -benzoyloxy-2 α,9 α,15 β -trihydroxy-5 α -isobutyryloxy-3 β,7 β,8 α -triacetoxy-pseudoolivine-6 (17), 11E-diene:
dissolving the compound 3 name 14 beta-benzoyloxy-2 alpha, 7 beta, 8 alpha, 9 alpha, 15 beta-pentahydroxy-5 alpha-isobutyryloxy-3 beta-acetoxyl-pseudo-white-elenane-6 (17), 11E-diene 22mg and 0.035mmol in dichloromethane 2mL, adding triethylamine 0.05mL,0.35mmol, acetic anhydride 10mg and 0.098mmol, stirring for 10 hours at room temperature, adding saturated sodium bicarbonate to quench, extracting with ethyl acetate, washing with water, saturated sodium bicarbonate and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating organic phase ethyl acetate, gradient eluting with silica gel column 200-300 meshes, eluting with petroleum ether and ethyl acetate in a volume ratio of 1.5:1 to obtain a white solid compound 4 name: 14 beta-benzoyloxy-2 alpha, 9 alpha, 15 beta-trihydroxy-5 alpha-isobutyryloxy-3 beta, 7 beta, 8 alpha-triacetoxy-pseudoolivine-6 (17), 11E-diene 8mg, yield 32%;
the mass spectrum and nuclear magnetic data of the compound are as follows: ESI (+) MS M/z 725.3162[ M + Na ]]+Molecular formula is C37H50O13.1H NMR(400MHz,CDCl3)δppm:2.23(1H,d,J＝15.0Hz,H-1α),2.11(1H,d,J＝15.2Hz,H-1β),5.31(1H,d,J＝3.6Hz,H-3),3.38(1H,m,H-4),5.70(1H,d,J＝3.0Hz,H-5),5.54(1H,s,H-7),5.20(1H,s,H-8),3.66(1H,s,H-9),5.87(1H,s,H-11),5.86(1H,d,J＝8.3Hz,H-12),2.88(1H,m,H-13),5.41(1H,s,H-14),1.28(3H,s,H3-16),4.98(1H,s,H-17α),4.62(1H,s,H-17β),1.07(3H,s,H3-18),1.30(3H,s,H3-19),1.13(3H,d,J＝7.1Hz,H3-20),2-OH:4.92(1H,s)；9-OH:4.80(1H,s)；15-OH:3.39(1H,s)；3-OAc:2.02(3H,s)；7-OAc:2.15(3H,s)；8-OAc:2.09(3H,s)；5-OiBu:2.14(1H,m,H-2'),0.80(3H,d,J＝7.0Hz,H-3'),0.70(3H,d,J＝7.0Hz,H-4')；14-OBz:8.01(2H,d,J＝7.0Hz,H-3',7'),7.47(2H,t,J＝7.3Hz,H-4',6'),7.53(1H,t,J＝7.3Hz,H-5').13C NMR(100MHz,CDCl3)δppm:54.6(C-1),83.5(C-2),82.9(C-3),43.9(C-4),71.7(C-5),144.8(C-6),69.1(C-7),73.3(C-8),81.8(C-9),41.3(C-10),134.3(C-11),131.1(C-12),37.1(C-13),79.5(C-14),78.0(C-15),24.3(C-16),109.4(C-17),27.5(C-18),24.0(C-19),24.0(C-20),3-OAc:169.6(CO),21.4(C-2')；7-OAc:170.4(CO),21.4(C-2')；8-OAc:170.3(CO),21.2(C-2')；5-OiBu:174.0(CO),34.2(C-2'),18.5(C-3'),18.7(C-4')；14-OBz:166.6(CO),129.8(C-2'),130.2(C-3',7'),128.8(C-4',6'),133.2(C-5')。
Example 5
Preparation of compound 5 name: 14 β -benzoyloxy-2 α,8 α,9 α,15 β, 17-pentahydroxy-5 α -isobutyryloxy-3 β -triacetoxy-6, 7 epoxy-pseudoolivine-11E-ene:
dissolving the compound 3 in 2mL of dichloromethane in a proportion of 30mg and 0.049mmol of 14 beta-benzoyloxy-2 alpha, 7 beta, 8 alpha, 9 alpha, 15 beta-pentahydroxy-5 alpha-isobutyryloxy-3 beta-acetoxyl-pseudo-white-elenane-6 (17) and 11E-diene, adding 17mg, 0.073mmol and 75% of m-chloroperoxybenzoic acid, stirring and reacting at room temperature for 24 hours, quenching saturated sodium thiosulfate, extracting ethyl acetate, washing with saturated sodium bicarbonate, water and saturated sodium chloride in sequence, drying anhydrous sodium sulfate, concentrating organic phase ethyl acetate, and performing gradient elution through a silica gel column with 200 meshes and 300 meshes, wherein the eluent is petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain 5 white solid compounds: 14 beta-benzoyloxy-2 alpha, 8 alpha, 9 alpha, 15 beta, 17-pentahydroxy-5 alpha-isobutyryloxy-3 beta-triacetoxy-6, 7 epoxy-pseudoelemene-11E-ene 15mg, yield 49%;
the nuclear magnetic data are:1H NMR(400MHz,CDCl3)δppm:2.17(1H,s,H-1α),2.13(1H,s,H-1β),5.32(1H,d,J＝3.6Hz,H-3),3.18(1H,m,H-4),5.83(1H,d,J＝3.2Hz,H-5),2.21(1H,m,H-6),4.19(1H,s,H-7),4.39(1H,s,H-8),3.61(1H,s,H-9),5.88(1H,d,J＝16.1Hz,H-11),5.77(1H,d,J＝9.3Hz,H-12),2.82(1H,m,H-13),5.41(1H,s,H-14),1.32(3H,s,H3-16),3.33(2H,m,H-17),1.11(3H,s,H3-18),1.24(3H,s,H3-19),1.12(3H,d,J＝7.7Hz,H3-20),2-OH:ND；3-OH:ND；7-OH:ND；8-OH:3.00(1H,d,J＝5.2Hz)；9-OH:3.16(1H,br s)；15-OH:ND；17-OH:ND；3-OAc:2.08(3H,s)；5-OiBu:2.12(1H,m,H-2'),0.67(3H,d,J＝7.0Hz,H-3'),0.80(3H,d,J＝7.0Hz,H-4')；14-OBz:8.05(2H,d,J＝7.1Hz,H-3',7'),7.46(2H,t,J＝7.6Hz,H-4',6'),7.55(1H,t,J＝7.4Hz,H-5').13C NMR(100MHz,CDCl3)δppm:54.4(C-1),78.4(C-2),83.2(C-3),42.6(C-4),67.2(C-5),44.9(C-6),64.3(C-7),71.2(C-8),83.5(C-9),40.9(C-10),135.3(C-11),130.3(C-12),37.1(C-13),79.3(C-14),84.0(C-15),24.3(C-16),63.2(C-17),27.1(C-18),23.7(C-19),23.9(C-20),3-OAc:170.4(CO),21.6(C-2')；5-OiBu:174.8(CO),34.0(C-2'),18.2(C-3'),18.7(C-4')；14-OBz:166.9(CO),129.7(C-2'),130.4(C-3',7'),128.6(C-4',6'),133.2(C-5')。
example 6
Preparation of compound 6 name: 14 β -benzoyloxy-2 α,7 β,9 α,15 β -tetrahydroxy-5 α -isobutyryloxy-3 β -acetoxy-8 α -3' -methyl-benzoyloxy-pseudoolivine-6 (17), 11E-diene:
dissolving a compound 3 name of 14 beta-benzoyloxy-2 alpha, 7 beta, 8 alpha, 9 alpha, 15 beta-pentahydroxy-5 alpha-isobutyryloxy-3 beta-acetoxyl-pseudo-white-elenane-6 (17), 11E-diene 65mg and 0.11mmol in pyridine 2mL, adding 3-methylbenzoyl chloride 32mg and 0.21mmol, stirring at room temperature for 1 hour, adding saturated sodium bicarbonate for quenching, extracting ethyl acetate, washing with water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating organic phase ethyl acetate, performing gradient elution through a silica gel column of 200 meshes and 300 meshes, and eluting petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain a white solid compound 6 name: 14 β -benzoyloxy-2 α,7 β,9 α,15 β -tetrahydroxy-5 α -isobutyryloxy-3 β -acetoxy-8 α -3' -methyl-benzoyloxy-pseudoolivine-6 (17), 11E-diene 51mg, yield 66%;
the nuclear magnetic data are:1H NMR(400MHz,CDCl3)δppm:2.19(1H,d,J＝14.9Hz,H-1α),2.12(1H,d,J＝14.8Hz,H-1β),5.24(1H,d,J＝4.7Hz,H-3),3.21(1H,m,H-4),5.82(1H,br s,H-5),4.71(1H,s,H-7),5.50(1H,s,H-8),3.83(1H,s,H-9),6.11(1H,d,J＝16.0Hz,H-11),5.87(1H,m,H-12),2.88(1H,m,H-13),5.40(1H,s,H-14),1.33(3H,s,H3-16),5.22(1H,s,H-17α),4.66(1H,s,H-17β),1.13(3H,s,H3-18),1.42(3H,s,H3-19),1.12(3H,d,J＝6.4Hz,H3-20),2-OH:ND；7-OH:4.19(1H,s)；9-OH:4.26(1H,s)；15-OH:3.55(1H,s)；3-OAc:2.06(3H,s)；5-OiBu:2.10(1H,m,H-2'),0.76(3H,d,J＝7.0Hz,H-3'),0.69(3H,d,J＝7.0Hz,H-4')；14-OBz:8.05(2H,d,J＝7.1Hz,H-3',7'),7.51(2H,t,J＝7.3Hz,H-4',6'),7.56(1H,t,J＝7.3Hz,H-5')；8-3’-CH3-BzO:7.92(1H,s,H-2'),7.34(1H,d,J＝7.5Hz,H-4'),7.29(1H,t,J＝7.8Hz,H-5'),7.92(1H,d,J＝7.3Hz,H-6'),2.37(3H,s,H-7').13C NMR(100MHz,CDCl3)δppm:54.2(C-1),78.8(C-2),83.8(C-3),44.0(C-4),71.9(C-5),147.6(C-6),67.9(C-7),74.1(C-8),82.7(C-9),41.2(C-10),135.1(C-11),130.6(C-12),37.6(C-13),79.6(C-14),83.9(C-15),24.7(C-16),108.5(C-17),27.8(C-18),24.1(C-19),23.8(C-20),3-OAc:171.2(CO),21.5(C-2')；5-OiBu:173.6(CO),34.2(C-2'),18.5(C-3'),18.5(C-4')；14-OBz:166.7(CO),129.7(C-2'),130.2(C-3',7'),128.9(C-4',6'),133.3(C-5')；8-3’-CH3-BzO:165.6(CO),130.6(C-1'),130.6(C-2'),138.3(C-3'),133.9(C-4'),128.4(C-5'),127.2(C-6'),21.5(C-7').
example 7
Preparation of compound 7 name: 14 β -benzoyloxy-2 α,8 α,9 α,15 β -tetrahydroxy-5 α -isobutyryloxy-3 β -acetoxy-7 β -3' -methylbenzoyloxy-pseudoolivine-6 (17), 11E-diene:
compound 6 was named: 14 beta-benzoyloxy-2 alpha, 7 beta, 9 alpha, 15 beta-tetrahydroxy-5 alpha-isobutyryloxy-3 beta-acetoxyl-8 alpha-3 '-methyl-benzoyloxy-pseudo-white olive-6 (17), 11E-diene is placed in methanol water solution for 6 days, concentrated and then subjected to gradient elution through 200-mesh and 300-mesh silica gel column, and the eluent is petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain a white solid compound 7, namely 14 beta-benzoyloxy-2 alpha, 8 alpha, 9 alpha, 15 beta-tetrahydroxy-5 alpha-isobutyryloxy-3 beta-acetoxyl-7 beta-3' -methyl benzoyloxy-pseudo-white olive-6 (17), and the yield of 11E-diene is 19%;
the nuclear magnetic data are:1H NMR(600MHz,CDCl3)δppm:2.27(1H,d,J＝15.0Hz,H-1α),2.14(1H,d,J＝15.0Hz,H-1β),5.42(1H,d,J＝3.4Hz,H-3),3.45(1H,m,H-4),5.75(1H,d,J＝2.4Hz,H-5),5.65(1H,s,H-7),4.25(1H,d,J＝4.1Hz,H-8),3.75(1H,s,H-9),5.95(1H,d,J＝16.1Hz,H-11),5.80(1H,m,H-12),2.89(1H,m,H-13),5.43(1H,s,H-14),1.32(3H,s,H3-16),5.11(1H,s,H-17α),4.69(1H,s,H-17β),1.06(3H,s,H3-18),1.25(3H,s,H3-19),1.14(3H,d,J＝7.0Hz,H3-20),2-OH:2.60(1H,s)；8-OH:2.49(1H,s)；9-OH:ND；15-OH:3.44(1H,s)；3-OAc:2.00(3H,s)；5-OiBu:2.16(1H,m,H-2'),0.85(3H,d,J＝7.0Hz,H-3'),0.68(3H,d,J＝7.0Hz,H-4')；14-OBz:8.00(2H,d,J＝7.8Hz,H-3',7'),7.46(2H,t,J＝7.6Hz,H-4',6'),7.56(1H,t,J＝7.4Hz,H-5')；7-3’-CH3-BzO:7.89(1H,s,H-2'),7.38(1H,d,J＝7.4Hz,H-4'),7.32(1H,t,J＝7.8Hz,H-5'),7.88(1H,d,J＝7.5Hz,H-6'),2.39(3H,s,H-7').13C NMR(150MHz,CDCl3)δppm:54.5(C-1),78.1(C-2),83.2(C-3),44.0(C-4),72.2(C-5),145.3(C-6),70.2(C-7),70.9(C-8),83.8(C-9),41.0(C-10),134.7(C-11),130.5(C-12),37.2(C-13),79.6(C-14),83.6(C-15),24.4(C-16),108.9(C-17),27.2(C-18),23.9(C-19),24.0(C-20),3-OAc:169.5(CO),21.4(C-2')；5-OiBu:175.0(CO),34.1(C-2'),18.3(C-3'),18.6(C-4')；14-OBz:166.5(CO),129.8(C-2'),130.1(C-3',7'),128.8(C-4',6'),133.2(C-5')；7-3’-CH3-BzO:165.6(CO),130.0(C-1'),130.5(C-2'),138.6(C-3'),134.5(C-4'),128.7(C-5'),127.2(C-6'),21.5(C-7').
example 8
Preparation of compound 8 name: 14 β -benzoyloxy-2 α,15 β -dihydroxy-5 α -isobutyryloxy-3 β,7 β,8 α,9 α -tetraacetoxy-pseudoolivine-6 (17), 11E-diene:
dissolving 3 compounds 14 beta-benzoyloxy-2 alpha, 7 beta, 8 alpha, 9 alpha, 15 beta-pentahydroxy-5 alpha-isobutyryloxy-3 beta-acetoxyl-pseudo-white-elenane-6 (17), 11E-diene 35mg and 0.057mmol in dichloromethane 2mL, adding triethylamine 0.05mL,0.35mmol, acetic anhydride 30mg,0.29mmol, 4-dimethylaminopyridine 1mg and 0.008mmol, stirring at room temperature for 2 hours, adding saturated sodium bicarbonate to quench, extracting with ethyl acetate, washing with water and saturated sodium chloride in sequence, drying with sodium sulfate, concentrating organic phase ethyl acetate, gradient eluting with silica gel column 200-300 meshes, and eluting with petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain 8 white solid compounds: 14 beta-benzoyloxy-2 alpha, 15 beta-dihydroxy-5 alpha-isobutyryloxy-3 beta, 7 beta, 8 alpha, 9 alpha-tetraacetoxy-pseudoolivine-6 (17), 11E-diene 37mg, yield 88%;
mass spectra and nuclear magnetic data were: ESI (+) MS M/z 767.3250[ M + Na ]]+Molecular formula is C39H52O14.1H NMR(400MHz,CDCl3)δppm:2.22(1H,d,J＝14.9Hz,H-1α),2.12(1H,d,J＝15.0Hz,H-1β),5.28(1H,d,J＝3.6Hz,H-3),3.36(1H,t,J＝3.5Hz,H-4),5.70(1H,d,J＝2.0Hz,H-5),5.57(1H,s,H-7),5.30(1H,s,H-8),5.01(1H,s,H-9),5.83(1H,d,J＝16.1Hz,H-11),5.90(1H,dd,J＝16.2,8.7Hz,H-12),2.89(1H,m,H-13),5.42(1H,s,H-14),1.29(3H,s,H3-16),4.98(1H,s,H-17α),4.61(1H,s,H-17β),0.91(3H,s,H3-18),1.41(3H,s,H3-19),1.13(3H,d,J＝7.0Hz,H3-20),2-OH:5.28(1H,br s)；15-OH:3.41(1H,s)；3-OAc:2.02(3H,s)；7-OAc:2.15(3H,s)；8-OAc:2.07(3H,s)；9-OAc:2.04(3H,s)；5-OiBu:2.14(1H,m,H-2'),0.69(3H,d,J＝7.0Hz,H-3'),0.78(3H,d,J＝7.0Hz,H-4')；14-OBz:8.01(2H,d,J＝7.1Hz,H-3',7'),7.47(2H,t,J＝7.4Hz,H-4',6'),7.54(1H,t,J＝7.3Hz,H-5').13C NMR(100MHz,CDCl3)δppm:54.5(C-1),78.2(C-2),82.8(C-3),43.8(C-4),71.5(C-5),144.6(C-6),68.6(C-7),70.9(C-8),80.9(C-9),41.0(C-10),134.1(C-11),131.8(C-12),37.2(C-13),79.4(C-14),83.6(C-15),24.4(C-16),109.6(C-17),27.0(C-18),23.8(C-19),23.9(C-20),3-OAc:169.7(CO),21.4(C-2')；7-OAc:170.3(CO),21.4(C-2')；8-OAc:170.1(CO),21.0(C-2')；9-OAc:169.9(CO),20.8(C-2')；5-OiBu:173.8(CO),34.1(C-2'),18.4(C-3'),18.6(C-4')；14-OBz:166.6(CO),129.7(C-2'),130.2(C-3',7'),128.9(C-4',6'),133.3(C-5')。
Example 9
Preparation of compound 9 name: 14 β -benzoyloxy-15 β -hydroxy-5 α -isobutyryloxy-2 α,3 β,7 β,8 α,9 α -pentaacetoxy-pseudoolivine-6 (17), 11E-diene:
compound 8 was named: dissolving 14 beta-benzoyloxy-2 alpha, 15 beta-dihydroxy-5 alpha-isobutyryloxy-3 beta, 7 beta, 8 alpha, 9 alpha-tetraacetoxy-pseudo-brunane-6 (17), 11E-diene 40mg and 0.054mmol in 2mL of pyridine, adding acetic anhydride 30mg,0.29mmol and 4-dimethylaminopyridine 1mg and 0.008mmol, refluxing and stirring for 24 hours, adding saturated sodium bicarbonate to quench, extracting ethyl acetate, washing with water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating organic phase ethyl acetate, performing gradient elution with a silica gel column of 200 meshes to 300 meshes, and eluting with petroleum ether and ethyl acetate in a volume ratio of 2:1 to obtain 9 white solid compounds: 14 beta-benzoyloxy-15 beta-hydroxy-5 alpha-isobutyryloxy-2 alpha, 3 beta, 7 beta, 8 alpha, 9 alpha-pentaacetoxy-pseudoolivine-6 (17), 11E-diene 21mg, 50% yield;
mass and nuclear magnetic dataComprises the following steps: ESI (+) MS M/z 809.3353[ M + Na ]]+Molecular formula is C41H54O15.1H NMR(400MHz,CDCl3)δppm:2.62(1H,d,J＝14.9Hz,H-1α),2.22(1H,d,J＝14.9Hz,H-1β),5.28(1H,d,J＝5.6Hz,H-3),3.23(1H,dd,J＝5.2,3.5Hz,H-4),5.71(1H,d,J＝2.0Hz,H-5),5.56(1H,s,H-7),5.33(1H,s,H-8),5.02(1H,s,H-9),5.89(1H,d,J＝16.0Hz,H-11),5.89(1H,dd,J＝16.0,8.5Hz,H-12),2.70(1H,m,H-13),5.40(1H,s,H-14),1.48(3H,s,H3-16),4.98(1H,s,H-17α),4.58(1H,s,H-17β),0.92(3H,s,H3-18),1.42(3H,s,H3-19),1.11(3H,d,J＝7.0Hz,H3-20),15-OH:3.46(1H,s)；2-OAc:2.12(3H,s)；3-OAc:2.00(3H,s)；7-OAc:2.10(3H,s)；8-OAc:2.05(3H,s)；9-OAc:2.04(3H,s)；5-OiBu:2.09(1H,m,H-2'),0.68(3H,d,J＝7.0Hz,H-3'),0.78(3H,d,J＝7.0Hz,H-4')；14-OBz:7.99(2H,d,J＝7.5Hz,H-3',7'),7.47(2H,t,J＝7.5Hz,H-4',6'),7.54(1H,t,J＝7.2Hz,H-5').13C NMR(100MHz,CDCl3)δppm:51.6(C-1),87.9(C-2),80.5(C-3),44.4(C-4),71.6(C-5),144.4(C-6),67.7(C-7),71.3(C-8),80.7(C-9),41.0(C-10),134.4(C-11),131.4(C-12),38.0(C-13),79.0(C-14),84.0(C-15),21.9(C-16),109.6(C-17),27.0(C-18),23.8(C-19),23.9(C-20),2-OAc:170.7(CO),22.5(C-2')；3-OAc:169.3(CO),21.3(C-2')；7-OAc:169.1(CO),21.2(C-2')；8-OAc:170.2(CO),21.0(C-2')；9-OAc:169.9(CO),20.8(C-2')；5-OiBu:173.7(CO),34.1(C-2'),18.4(C-3'),18.5(C-4')；14-OBz:166.5(CO),129.5(C-2'),130.2(C-3',7'),128.9(C-4',6'),133.4(C-5')。
Example 10
Preparation of compound 10 name: 14 β -benzoyloxy-15 β -hydroxy-5 α -isobutyryloxy-3 β,7 β,8 α,9 α -tetraacetoxy-2 α -3' -methyl-benzoyloxy-pseudoolivine-6 (17), 11E-diene:
compound 8 was named: dissolving 14 beta-benzoyloxy-2 alpha, 15 beta-dihydroxy-5 alpha-isobutyryloxy-3 beta, 7 beta, 8 alpha, 9 alpha-tetraacetoxy-pseudo-brunane-6 (17), 11E-diene 50mg and 0.067mmol in pyridine 2mL, adding 3-methylbenzoyl chloride 31mg,0.20mmol and 4-dimethylaminopyridine 1mg and 0.008mmol, refluxing and stirring for 24 hours, adding saturated sodium bicarbonate to quench, extracting with ethyl acetate, washing with water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating organic phase ethyl acetate, and gradient eluting with silica gel column 200-300 meshes, wherein the eluent is petroleum ether and ethyl acetate in a volume ratio of 2:1, and 10 white solid compounds are obtained: 14 β -benzoyloxy-15 β -hydroxy-5 α -isobutyryloxy-3 β,7 β,8 α,9 α -tetraacetoxy-2 α -3' -methyl-benzoyloxy-pseudoolivine-6 (17), 11E-diene 30mg, yield 52%;
mass spectra and nuclear magnetic data were: ESI (+) MS M/z 885.3671[ M + Na ]]+Molecular formula is C47H58O15.1H NMR(400MHz,CDCl3)δppm:2.63(1H,d,J＝15.4Hz,H-1α),2.52(1H,d,J＝15.2Hz,H-1β),5.83(1H,d,J＝5.0Hz,H-3),3.19(1H,dd,J＝5.5,3.5Hz,H-4),5.76(1H,s,H-5),5.56(1H,s,H-7),5.36(1H,s,H-8),5.02(1H,s,H-9),5.76(1H,d,J＝15.8Hz,H-11),5.88(1H,dd,J＝16.8,9.8Hz,H-12),2.59(1H,m,H-13),5.42(1H,s,H-14),1.65(3H,s,H3-16),5.01(1H,s,H-17α),4.63(1H,s,H-17β),0.86(3H,s,H3-18),1.43(3H,s,H3-19),1.06(3H,d,J＝7.0Hz,H3-20),15-OH:3.50(1H,s)；2-3’-CH3-BzO:8.13(1H,s,H-2'),7.36(1H,d,J＝7.6Hz,H-4'),7.30(1H,t,J＝7.6Hz,H-5'),8.04(1H,d,J＝7.6Hz,H-6'),2.40(3H,s,H-7')；3-OAc:2.04(3H,s)；7-OAc:2.18(3H,s)；8-OAc:2.07(3H,s)；9-OAc:2.03(3H,s)；5-OiBu:2.12(1H,m,H-2'),0.72(3H,d,J＝7.0Hz,H-3'),0.79(3H,d,J＝7.0Hz,H-4')；14-OBz:7.99(2H,d,J＝7.1Hz,H-3',7'),7.48(2H,t,J＝7.4Hz,H-4',6'),7.55(1H,t,J＝7.3Hz,H-5').13C NMR(100MHz,CDCl3)δppm:52.2(C-1),88.8(C-2),80.9(C-3),44.3(C-4),71.6(C-5),144.5(C-6),68.1(C-7),71.3(C-8),80.8(C-9),41.0(C-10),134.3(C-11),131.5(C-12),38.1(C-13),79.0(C-14),84.1(C-15),21.1(C-16),109.4(C-17),27.0(C-18),23.9(C-19),23.8(C-20),2-3’-CH3-BzO:166.2(CO),131.2(C-1'),131.0(C-2'),138.1(C-3'),133.8(C-4'),128.2(C-5'),127.5(C-6'),21.4(C-7')；3-OAc:169.6(CO),21.4(C-2')；7-OAc:169.3(CO),21.2(C-2')；8-OAc:170.2(CO),21.0(C-2')；9-OAc:169.8(CO),20.8(C-2')；5-OiBu:173.8(CO),34.2(C-2'),18.5(C-3'),18.5(C-4')；14-OBz:166.4(CO),129.5(C-2'),130.2(C-3',7'),129.0(C-4',6'),133.4(C-5')。
Example 11
Preparation of compound 11 name: 14 β -benzoyloxy-15 β -hydroxy-5 α -isobutyryloxy-3 β,7 β,8 α,9 α -tetraacetoxy-2 α -isonicotinyloxy-pseudoCanane-6 (17), 11E-diene:
compound 8 was named: dissolving 14 beta-benzoyloxy-2 alpha, 15 beta-dihydroxy-5 alpha-isobutyryloxy-3 beta, 7 beta, 8 alpha, 9 alpha-tetraacetoxy-pseudocanary-6 (17), 11E-diene 55mg and 0.074mmol in 2mL of pyridine, adding 31mg,0.22mmol and 4-dimethylaminopyridine 0.008mmol, refluxing and stirring for 4 hours, adding saturated sodium bicarbonate to quench, extracting with ethyl acetate, washing with water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating organic phase ethyl acetate, performing gradient elution with a silica gel column of 200 meshes and 300 meshes, and eluting with petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain 11 white solid compounds: 14 beta-benzoyloxy-15 beta-hydroxy-5 alpha-isobutyryloxy-3 beta, 7 beta, 8 alpha, 9 alpha-tetraacetoxy-2 alpha-isonicotinyloxy-pseudoolivine-6 (17), 11E-diene 46mg, yield 73%;
mass spectra and nuclear magnetic data were: ESI (+) MS M/z 872.3452[ M + Na ]]+Molecular formula is C45H55NO15.1H NMR(400MHz,CDCl3)δppm:2.60(1H,d,J＝14.8Hz,H-1α),2.51(1H,d,J＝15.0Hz,H-1β),5.80(1H,d,J＝6.5Hz,H-3),3.20(1H,dd,J＝5.7,3.4Hz,H-4),5.75(1H,d,J＝3.8Hz,H-5),5.54(1H,s,H-7),5.34(1H,s,H-8),5.02(1H,s,H-9),5.77(1H,d,J＝16.4Hz,H-11),5.89(1H,dd,J＝16.2,9.2Hz,H-12),2.59(1H,m,H-13),5.43(1H,s,H-14),1.64(3H,s,H3-16),5.01(1H,s,H-17α),4.62(1H,s,H-17β),0.86(3H,s,H3-18),1.43(3H,s,H3-19),1.07(3H,d,J＝7.0Hz,H3-20),15-OH:3.47(1H,s)；2-OiNic:8.10(2H,d,J＝6.0Hz,H-2',6’),8.77(2H,d,J＝5.9Hz,H-3',5’)；3-OAc:2.04(3H,s)；7-OAc:2.16(3H,s)；8-OAc:2.07(3H,s)；9-OAc:2.04(3H,s)；5-OiBu:2.11(1H,m,H-2'),0.71(3H,d,J＝7.0Hz,H-3'),0.78(3H,d,J＝7.0Hz,H-4')；14-OBz:7.98(2H,d,J＝7.2Hz,H-3',7'),7.48(2H,t,J＝7.5Hz,H-4',6'),7.55(1H,t,J＝7.3Hz,H-5').13C NMR(100MHz,CDCl3)δppm:52.0(C-1),90.2(C-2),80.5(C-3),44.3(C-4),71.4(C-5),144.6(C-6),68.0(C-7),71.2(C-8),80.8(C-9),41.0(C-10),134.4(C-11),131.3(C-12),38.3(C-13),78.8(C-14),84.0(C-15),21.2(C-16),109.5(C-17),27.0(C-18),23.8(C-19),23.9(C-20),2-OiNic:164.3(CO),138.9(C-1'),123.8(C-2',6’),150.3(C-3',5’)；3-OAc:169.8(CO),21.3(C-2')；7-OAc:169.7(CO),21.3(C-2')；8-OAc:170.2(CO),21.0(C-2')；9-OAc:169.6(CO),20.8(C-2')；5-OiBu:173.8(CO),34.2(C-2'),18.4(C-3'),18.5(C-4')；14-OBz:166.4(CO),129.4(C-2'),130.1(C-3',7'),129.0(C-4',6'),133.5(C-5')。
Example 12
Preparation of compound 12 name: 14 β -benzoyloxy-15 β -hydroxy-5 α -isobutyryloxy-3 β,7 β,8 α,9 α -tetraacetoxy-2 α -pivaloyloxy-pseudoolivine-6 (17), 11E-diene:
dissolving the compound 8, namely 14 beta-benzoyloxy-2 alpha, 15 beta-dihydroxy-5 alpha-isobutyryloxy-3 beta, 7 beta, 8 alpha, 9 alpha-tetraacetoxy-pseudoolivine-6 (17), 11E-diene 155mg and 0.21mmol in 3mL of pyridine, adding pivaloyl chloride 51mg,0.42mmol, 4-dimethylaminopyridine 3mg and 0.025mmol, refluxing and stirring for 18 hours, adding saturated sodium bicarbonate to quench, extracting ethyl acetate, washing with water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating organic phase ethyl acetate, and performing gradient elution through a silica gel column with 200 meshes and 300 meshes, wherein the eluent is petroleum ether and ethyl acetate in a volume ratio of 3:1 to obtain 12 white solid compounds: 14 beta-benzoyloxy-15 beta-hydroxy-5 alpha-isobutyryloxy-3 beta, 7 beta, 8 alpha, 9 alpha-tetraacetoxy-2 alpha-pivaloyloxy-pseudoolivine-6 (17), 11E-diene 80mg, yield 46%;
mass spectra and nuclear magnetic data were: ESI (+) MS M/z 851.3829[ M + Na ]]+Molecular formula is C44H60O15.1H NMR(400MHz,CDCl3)δppm:2.56(1H,d,J＝15.1Hz,H-1α),2.29(1H,d,J＝15.1Hz,H-1β),5.64(1H,d,J＝5.7Hz,H-3),3.18(1H,dd,J＝5.5,3.7Hz,H-4),5.71(1H,d,J＝2.8Hz,H-5),5.52(1H,s,H-7),5.34(1H,s,H-8),5.00(1H,s,H-9),5.84(1H,d,J＝16.4Hz,H-11),5.90(1H,dd,J＝16.4,7.8Hz,H-12),2.64(1H,m,H-13),5.39(1H,s,H-14),1.48(3H,s,H3-16),4.96(1H,s,H-17α),4.58(1H,s,H-17β),0.91(3H,s,H3-18),1.43(3H,s,H3-19),1.11(3H,d,J＝7.0Hz,H3-20),15-OH:3.51(1H,s)；2-OPiv:1.26(9H,s,H-3',4’,5’)；3-OAc:2.00(3H,s)；7-OAc:2.09(3H,s)；8-OAc:2.07(3H,s)；9-OAc:2.03(3H,s)；5-OiBu:2.09(1H,m,H-2'),0.69(3H,d,J＝7.0Hz,H-3'),0.77(3H,d,J＝7.0Hz,H-4')；14-OBz:7.99(2H,d,J＝7.0Hz,H-3',7'),7.48(2H,t,J＝7.3Hz,H-4',6'),7.55(1H,t,J＝7.3Hz,H-5').13C NMR(100MHz,CDCl3)δppm:51.7(C-1),87.7(C-2),80.7(C-3),44.4(C-4),71.7(C-5),144.2(C-6),67.8(C-7),71.2(C-8),80.9(C-9),41.0(C-10),134.3(C-11),131.6(C-12),38.2(C-13),79.1(C-14),84.1(C-15),21.3(C-16),109.4(C-17),27.1(C-18),23.8(C-19),23.9(C-20),2-OPiv:178.0(CO),39.5(C-2'),27.2(C-3',4’,5’)；3-OAc:169.4(CO),21.3(C-2')；7-OAc:168.7(CO),21.1(C-2')；8-OAc:170.1(CO),21.0(C-2')；9-OAc:169.8(CO),20.7(C-2')；5-OiBu:173.7(CO),34.2(C-2'),18.4(C-3'),18.5(C-4')；14-OBz:166.5(CO),129.5(C-2'),130.2(C-3',7'),129.0(C-4',6'),133.4(C-5')。
Example 13
Preparation of compound 13 name: 14 β -benzoyloxy-2 α,7 β,9 α,15 β -tetrahydroxy-5 α -isobutyryloxy-3 β -acetoxy-8 α -pivaloyloxy-pseudoolivine-6 (17), 11E-diene:
dissolving a compound 3 name of 14 beta-benzoyloxy-2 alpha, 7 beta, 8 alpha, 9 alpha, 15 beta-pentahydroxy-5 alpha-isobutyryloxy-3 beta-acetoxyl-pseudo-white-elenane-6 (17), 11E-diene 65mg and 0.11mmol in pyridine 2mL, adding pivaloyl chloride 25mg and 0.21mmol, stirring at room temperature for 2 hours, adding saturated sodium bicarbonate for quenching, extracting with ethyl acetate, washing with water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating organic phase ethyl acetate, performing gradient elution with a silica gel column of 200 meshes and 300 meshes, and eluting with petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain a white solid compound 13 name: 14 beta-benzoyloxy-2 alpha, 7 beta, 9 alpha, 15 beta-tetrahydroxy-5 alpha-isobutyryloxy-3 beta-acetoxy-8 alpha-pivaloyloxy-pseudoolivine-6 (17), 11E-diene 44mg, yield 60%;
the nuclear magnetic data are:1H NMR(400MHz,CDCl3)δppm:2.17(1H,d,J＝15.0Hz,H-1α),2.11(1H,d,J＝14.9Hz,H-1β),5.15(1H,d,J＝5.3Hz,H-3),3.11(1H,m,H-4),5.71(1H,d,J＝2.3Hz,H-5),4.55(1H,s,H-7),5.20(1H,s,H-8),3.68(1H,s,H-9),5.93(1H,d,J＝16.0Hz,H-11),5.79(1H,dd,J＝16.0,9.4Hz,H-12),2.83(1H,dd,J＝8.9,7.3Hz,H-13),5.37(1H,s,H-14),1.32(3H,s,H3-16),5.16(1H,s,H-17α),4.66(1H,s,H-17β),1.10(3H,s,H3-18),1.32(3H,s,H3-19),1.12(3H,d,J＝7.0Hz,H3-20),2-OH:ND；7-OH:3.89(1H,br s)；9-OH:4.22(1H,s)；15-OH:3.52(1H,s)；3-OAc:2.05(3H,s)；5-OiBu:2.11(1H,m,H-2'),0.66(3H,d,J＝7.0Hz,H-3'),0.79(3H,d,J＝7.0Hz,H-4')；8-OPiv:1.19(9H,s,H-3',4’,5’)；14-OBz:8.01(2H,d,J＝7.2Hz,H-3',7'),7.47(2H,t,J＝7.4Hz,H-4',6'),7.53(1H,t,J＝7.3Hz,H-5').13C NMR(100MHz,CDCl3)δppm:54.1(C-1),78.6(C-2),83.7(C-3),44.2(C-4),72.0(C-5),147.3(C-6),68.5(C-7),73.1(C-8),82.5(C-9),41.3(C-10),135.0(C-11),130.8(C-12),37.5(C-13),79.7(C-14),83.8(C-15),24.6(C-16),108.5(C-17),27.4(C-18),24.3(C-19),23.9(C-20),3-OAc:171.0(CO),21.5(C-2')；5-OiBu:173.6(CO),34.1(C-2'),18.5(C-3'),18.6(C-4')；8-OPiv:176.9(CO),39.4(C-2'),27.4(C-3',4’,5’)；14-OBz:166.7(CO),129.6(C-2'),130.2(C-3',7'),128.9(C-4',6'),133.3(C-5')。
example 14
Preparation of compound 14 name: 14 β -benzoyloxy-2 α,15 β -dihydroxy-5 α -isobutyryloxy-3 β,7 β,9 α -triacetoxy-8 α -3' -methyl-benzoyloxy-pseudoolivine-6 (17), 11E-diene:
compound 6 was named: 14 beta-benzoyloxy-2 alpha, 7 beta, 9 alpha, 15 beta-tetrahydroxy-5 alpha-isobutyryloxy-3 beta-acetoxy-8 alpha-3' -methyl-benzoyloxy-pseudowhite olive-6 (17), 11E-diene 30mg,0.041mmol are dissolved in dichloromethane 2mL, triethylamine 0.05mL,0.35mmol, acetic anhydride 20mg,2.04mmol, 4-dimethylaminopyridine 1mg,0.008mmol are added and stirred at room temperature for 2 hours, adding saturated sodium bicarbonate to quench, extracting with ethyl acetate, washing with water and saturated sodium chloride, drying with anhydrous sodium sulfate, concentrating organic phase ethyl acetate, and then the white solid compound 14 is obtained by gradient elution through a silica gel column with 200-mesh and 300-mesh, and the eluent is petroleum ether and ethyl acetate with the volume ratio of 1: 14 β -benzoyloxy-2 α,15 β -dihydroxy-5 α -isobutyryloxy-3 β,7 β,9 α -triacetoxy-8 α -3' -methyl-benzoyloxy-pseudoolivine-6 (17), 11E-diene 28mg, 84% yield;
the nuclear magnetic data of the compound are:1H NMR(400MHz,CDCl3)δppm:2.24(1H,d,J＝15.0Hz,H-1α),2.14(1H,d,J＝14.9Hz,H-1β),5.29(1H,d,J＝3.9Hz,H-3),3.39(1H,t,J＝3.6Hz,H-4),5.78(1H,d,J＝3.0Hz,H-5),5.68(1H,s,H-7),5.52(1H,s,H-8),5.16(1H,s,H-9),5.91(1H,d,J＝16.1Hz,H-11),5.95(1H,d,J＝16.0Hz,H-12),2.91(1H,m,H-13),5.44(1H,s,H-14),1.30(3H,s,H3-16),5.02(1H,s,H-17α),4.60(1H,s,H-17β),0.94(3H,s,H3-18),1.53(3H,s,H3-19),1.14(3H,d,J＝7.0Hz,H3-20),2-OH:ND；15-OH:3.43(1H,s)；3-OAc:2.00(3H,s)；7-OAc:2.22(3H,s)；9-OAc:2.06(3H,s)；5-OiBu:2.09(1H,m,H-2'),0.66(3H,d,J＝7.0Hz,H-3'),0.74(3H,d,J＝7.0Hz,H-4')；14-OBz:8.03(2H,d,J＝7.3Hz,H-3',7'),7.50(2H,t,J＝7.5Hz,H-4',6'),7.55(1H,t,J＝7.3Hz,H-5')；8-3’-CH3-BzO:7.88(1H,s,H-2'),7.35(1H,d,J＝7.5Hz,H-4'),7.31(1H,t,J＝7.6Hz,H-5'),7.84(1H,d,J＝7.6Hz,H-6'),2.38(3H,s,H-7').13C NMR(100MHz,CDCl3)δppm:54.7(C-1),78.2(C-2),82.9(C-3),43.8(C-4),71.3(C-5),144.8(C-6),68.7(C-7),71.6(C-8),80.8(C-9),41.0(C-10),134.2(C-11),131.7(C-12),37.3(C-13),79.2(C-14),83.6(C-15),24.5(C-16),109.9(C-17),27.3(C-18),23.7(C-19),23.9(C-20),3-OAc:169.8(CO),21.4(C-2')；7-OAc:170.2(CO),21.3(C-2')；9-OAc:169.7(CO),20.8(C-2')；5-OiBu:173.8(CO),34.1(C-2'),18.4(C-3'),18.5(C-4')；14-OBz:166.6(CO),129.7(C-2'),130.2(C-3',7'),128.9(C-4',6'),133.3(C-5')；8-3’-CH3-BzO:165.7(CO),130.2(C-1'),130.8(C-2'),138.3(C-3'),134.0(C-4'),128.5(C-5'),127.2(C-6'),21.6(C-7')。
example 15
Preparation of compound 15 name: 14 β -benzoyloxy-15 β -hydroxy-5 α -isobutyryloxy-2 α,3 β,7 β,9 α -tetraacetoxy-8 α -3' -methyl-benzoyloxy-pseudoolivine-6 (17), 11E-diene:
dissolving 14 name of a compound 14 of 14 beta-benzoyloxy-2 alpha, 15 beta-dihydroxy-5 alpha-isobutyryloxy-3 beta, 7 beta, 9 alpha-triacetoxy-8 alpha-3' -methyl-benzoyloxy-pseudo-white olive-6 (17), 11E-diene 51mg and 0.062mmol in pyridine 3mL, adding acetic anhydride 20mg,0.196mmol, 4-dimethylamino pyridine 1mg and 0.008mmol, refluxing and stirring for 48 hours, adding saturated sodium bicarbonate to quench, extracting with ethyl acetate, washing with water and saturated sodium chloride, drying with anhydrous sodium sulfate, concentrating organic phase ethyl acetate, and then the white solid compound 15 is obtained by gradient elution through a silica gel column with 200-mesh and 300-mesh, and the eluent is petroleum ether and ethyl acetate with the volume ratio of 2: 1: 14 β -benzoyloxy-15 β -hydroxy-5 α -isobutyryloxy-2 α,3 β,7 β,9 α -tetraacetoxy-8 α -3' -methyl-benzoyloxy-pseudoolivine-6 (17), 11E-diene 26mg, yield 48%;
the nuclear magnetic data are:1H NMR(400MHz,CDCl3)δppm:2.63(1H,d,J＝14.8Hz,H-1α),2.26(1H,d,J＝14.8Hz,H-1β),5.60(1H,d,J＝5.7Hz,H-3),3.28(1H,dd,J＝5.4,3.5Hz,H-4),5.81(1H,br s,H-5),5.68(1H,s,H-7),5.56(1H,s,H-8),5.18(1H,s,H-9),5.98(1H,m,H-11),5.98(1H,m,H-12),2.76(1H,m,H-13),5.43(1H,s,H-14),1.49(3H,s,H3-16),5.03(1H,s,H-17α),4.58(1H,s,H-17β),0.96(3H,s,H3-18),1.55(3H,s,H3-19),1.13(3H,d,J＝7.0Hz,H3-20),15-OH:3.47(1H,s)；2-OAc:2.13(3H,s)；3-OAc:1.98(3H,s)；7-OAc:2.17(3H,s)；9-OAc:2.06(3H,s)；5-OiBu:2.05(1H,m,H-2'),0.67(3H,d,J＝7.0Hz,H-3'),0.74(3H,d,J＝7.0Hz,H-4')；14-OBz:8.02(2H,d,J＝7.2Hz,H-3',7'),7.50(2H,t,J＝7.6Hz,H-4',6'),7.56(1H,t,J＝7.3Hz,H-5')；8-3’-CH3-BzO:7.87(1H,s,H-2'),7.34(1H,d,J＝7.5Hz,H-4'),7.30(1H,t,J＝7.6Hz,H-5'),7.84(1H,d,J＝7.6Hz,H-6'),2.38(3H,s,H-7').13C NMR(100MHz,CDCl3)δppm:51.8(C-1),88.0(C-2),80.5(C-3),44.4(C-4),71.4(C-5),144.6(C-6),67.8(C-7),71.9(C-8),80.7(C-9),41.0(C-10),134.5(C-11),131.4(C-12),38.0(C-13),78.9(C-14),84.0(C-15),22.0(C-16),109.9(C-17),27.2(C-18),23.7(C-19),23.9(C-20),2-OAc:170.7(CO),22.6(C-2')；3-OAc:169.4(CO),21.3(C-2')；7-OAc:168.9(CO),21.2(C-2')；9-OAc:169.7(CO),20.8(C-2')；5-OiBu:173.7(CO),34.1(C-2'),18.4(C-3'),18.4(C-4')；14-OBz:166.5(CO),129.6(C-2'),130.2(C-3',7'),129.0(C-4',6'),133.4(C-5')；8-3’-CH3-BzO:165.7(CO),130.2(C-1'),130.7(C-2'),138.2(C-3'),133.9(C-4'),128.4(C-5'),127.2(C-6'),21.6(C-7')。
example 16
Preparation of compound 16 name: 14 β -benzoyloxy-2 α,15 β -dihydroxy-5 α -isobutyryloxy-3 β,7 β,9 α -triacetoxy-8 α -pivaloyloxy-pseudoolivine-6 (17), 11E-diene:
dissolving 13 compounds, namely 14 beta-benzoyloxy-2 alpha, 7 beta, 9 alpha, 15 beta-tetrahydroxy-5 alpha-isobutyryloxy-3 beta-acetoxyl-8 alpha-pivaloyloxy-pseudoCanane-6 (17), 11E-diene 42mg and 0.060mmol in dichloromethane 2mL, adding triethylamine 0.05mL,0.35mmol, acetic anhydride 24mg,0.24mmol, 4-dimethylaminopyridine 1mg and 0.008mmol, stirring at room temperature for 2 hours, adding saturated sodium bicarbonate to quench, extracting with ethyl acetate, washing with water and saturated sodium chloride, drying with anhydrous sodium sulfate, concentrating organic phase ethyl acetate, and then the white solid compound 16 is obtained by gradient elution through a silica gel column with 200-mesh and 300-mesh, and the eluent is petroleum ether and ethyl acetate with the volume ratio of 1: 14 beta-benzoyloxy-2 alpha, 15 beta-dihydroxy-5 alpha-isobutyryloxy-3 beta, 7 beta, 9 alpha-triacetoxy-8 alpha-pivaloyloxy-pseudoolivine-6 (17), 11E-diene 40mg, yield 85%;
the nuclear magnetic data of the compound are:1H NMR(400MHz,CDCl3)δppm:2.21(1H,d,J＝14.9Hz,H-1α),2.12(1H,d,J＝14.8Hz,H-1β),5.26(1H,d,J＝3.9Hz,H-3),3.33(1H,t,J＝3.7Hz,H-4),5.70(1H,d,J＝2.7Hz,H-5),5.56(1H,s,H-7),5.21(1H,s,H-8),5.02(1H,s,H-9),5.88(1H,d,J＝16.1Hz,H-11),5.88(1H,d,J＝16.0Hz,H-12),2.87(1H,dd,J＝8.8,7.3Hz,H-13),5.41(1H,s,H-14),1.28(3H,s,H3-16),4.97(1H,s,H-17α),4.61(1H,s,H-17β),0.91(3H,s,H3-18),1.44(3H,s,H3-19),1.12(3H,d,J＝7.0Hz,H3-20),2-OH:ND；15-OH:3.41(1H,s)；3-OAc:2.00(3H,s)；7-OAc:2.13(3H,s)；9-OAc:2.03(3H,s)；5-OiBu:2.12(1H,m,H-2'),0.66(3H,d,J＝7.0Hz,H-3'),0.78(3H,d,J＝7.0Hz,H-4')；14-OBz:7.99(2H,d,J＝7.2Hz,H-3',7'),7.47(2H,t,J＝7.6Hz,H-4',6'),7.53(1H,t,J＝7.4Hz,H-5')；8-OPiv:1.18(9H,s,H-3',4’,5’).13C NMR(100MHz,CDCl3)δppm:54.5(C-1),78.2(C-2),82.9(C-3),43.8(C-4),71.4(C-5),145.1(C-6),68.9(C-7),70.8(C-8),80.5(C-9),40.9(C-10),134.3(C-11),131.7(C-12),37.2(C-13),79.3(C-14),83.6(C-15),24.4(C-16),109.4(C-17),27.1(C-18),23.8(C-19),23.9(C-20),3-OAc:169.7(CO),21.4(C-2')；7-OAc:170.2(CO),21.2(C-2')；9-OAc:169.6(CO),20.8(C-2')；5-OiBu:173.8(CO),34.0(C-2'),18.4(C-3'),18.5(C-4')；14-OBz:166.6(CO),129.7(C-2'),130.1(C-3',7'),128.9(C-4',6'),133.3(C-5')；8-OPiv:177.3(CO),39.3(C-2'),27.3(C-3',4’,5’)。
example 17
Preparation of compound 17 name: 14 beta-benzoyloxy-15 beta-hydroxy-5 alpha-isobutyryloxy-2 alpha, 3 beta, 7 beta, 9 alpha-tetraacetoxy-8 alpha-pivaloyloxy-pseudoolivine-6 (17), 11E-diene
Dissolving 16 compounds 14 beta-benzoyloxy-2 alpha, 15 beta-dihydroxy-5 alpha-isobutyryloxy-3 beta, 7 beta, 9 alpha-triacetoxy-8 alpha-pivaloyloxy-pseudo-white-elenane-6 (17), 11E-diene 40mg and 0.051mmol in pyridine 3mL, adding 16mg,0.157mmol, 4-dimethylaminopyridine 1mg and 0.008mmol, refluxing and stirring for 48 hours, adding saturated sodium bicarbonate for quenching, extracting with ethyl acetate, washing with water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating organic phase ethyl acetate, performing gradient elution with a silica gel column of 200-300 meshes, and eluting with petroleum ether and ethyl acetate in a volume ratio of 2:1 to obtain a white solid compound 17: 14 beta-benzoyloxy-15 beta-hydroxy-5 alpha-isobutyryloxy-2 alpha, 3 beta, 7 beta, 9 alpha-tetraacetoxy-8 alpha-pivaloyloxy-pseudoolivine-6 (17), 11E-diene 19mg, 45% yield;
the nuclear magnetic data are:1H NMR(400MHz,CDCl3)δppm:2.60(1H,d,J＝14.9Hz,H-1α),2.23(1H,d,J＝14.9Hz,H-1β),5.57(1H,d,J＝5.8Hz,H-3),3.21(1H,dd,J＝5.3,3.6Hz,H-4),5.72(1H,d,J＝2.1Hz,H-5),5.56(1H,s,H-7),5.27(1H,s,H-8),5.04(1H,s,H-9),5.91(1H,m,H-11),5.91(1H,m,H-12),2.71(1H,br s,H-13),5.40(1H,s,H-14),1.48(3H,s,H3-16),4.98(1H,s,H-17α),4.59(1H,s,H-17β),0.93(3H,s,H3-18),1.47(3H,s,H3-19),1.12(3H,d,J＝7.0Hz,H3-20),15-OH:3.44(1H,s)；2-OAc:2.12(3H,s)；3-OAc:2.00(3H,s)；7-OAc:2.09(3H,s)；9-OAc:2.04(3H,s)；5-OiBu:2.08(1H,m,H-2'),0.66(3H,d,J＝7.0Hz,H-3'),0.77(3H,d,J＝7.0Hz,H-4')；14-OBz:7.99(2H,d,J＝7.5Hz,H-3',7'),7.47(2H,t,J＝7.6Hz,H-4',6'),7.54(1H,t,J＝7.3Hz,H-5')；8-OPiv:1.17(9H,s,H-3',4’,5’).13C NMR(100MHz,CDCl3)δppm:51.7(C-1),87.9(C-2),80.6(C-3),44.4(C-4),71.5(C-5),144.8(C-6),68.0(C-7),71.1(C-8),80.4(C-9),41.0(C-10),134.5(C-11),131.4(C-12),37.9(C-13),78.9(C-14),83.9(C-15),21.9(C-16),109.4(C-17),27.0(C-18),23.9(C-19),24.0(C-20),2-OAc:170.7(CO),22.5(C-2')；3-OAc:169.3(CO),21.3(C-2')；7-OAc:168.9(CO),21.1(C-2')；9-OAc:169.7(CO),20.7(C-2')；5-OiBu:173.8(CO),34.1(C-2'),18.4(C-3'),18.5(C-4')；14-OBz:166.5(CO),129.6(C-2'),130.2(C-3',7'),129.0(C-4',6'),133.4(C-5')；8-OPiv:177.3(CO),39.3(C-2'),27.3(C-3',4’,5’)。
example 18
The compounds 1 to 17 obtained in examples 1 to 17 were tested for the activity of reversing tumor multidrug resistance:
in the experiment, 17 novel pseudoolivine diterpenoid derivatives are selected to be combined with an anti-tumor drug adriamycin (DOX), growth inhibition on drug-resistant cells is detected before and after combination, and multi-drug resistance reversal activity test is carried out;
the experimental method comprises the following steps: MCF7/ADR cells in a logarithmic growth phase are inoculated on a 96-well microplate (100 mu L per well) at the density of 5000 cells/well, and are incubated in an incubator at the temperature of 37 ℃ for 24 hours, then doxorubicin and a test monomer compound or positive control drugs verapamil VRP and ES3 are added, 100 mu L per well is provided with 7 concentration gradients, 6 multiple wells are provided, and a blank control group and a solvent dimethyl sulfoxide (DMSO) control group are provided; tumor cells were incubated at 37 ℃ and 5% CO2Culturing for 48 hr under the condition, discarding supernatant, adding thiazole blue (MTT) solution (5mg/mL, prepared with physiological saline, mixing with complete culture medium at a ratio of 1:9, and mixing at a concentration of 100 μ L per well), and culturing at 37 deg.C with 5% CO2Continuously culturing for 4h under the condition, discarding the supernatant, adding 150 μ L of dimethyl sulfoxide (DMSO) into each hole, detecting the absorbance value (A) of 570nm in each hole by using a microplate reader after formazan is dissolved, and calculating the monomer compound to be tested for swelling according to the following formulaInhibition of tumor cell growth: inhibition (%) - (a control group-a administration group)/a control group × 100%; inverse multiple (RF) IC50(Adriamycin)/IC50(doxorubicin + compounds);
the experimental results are as follows: half-growth inhibition and fold reversal of MCF7/ADR cells by the combination of compounds 1-17 and doxorubicin are shown in Table 1:
TABLE 1 half-growth inhibition and fold-reversal RF values of Compounds 1-17 in combination with Adriamycin on Adriamycin-resistant human Breast cancer cells MCF7/ADR
Figure BDA0003118961380000211
Figure BDA0003118961380000221
As shown in Table 1, when doxorubicin was used in combination with compounds 1, 2, 6,7, 8,9, 10, 11,12, 14, 15, 16 and 17, respectively, IC was compared with doxorubicin alone50The value is significantly reduced; under the same concentration (10 mu M), the compounds 1, 10, 11,12, 14, 15, 16 and 17 have stronger multidrug resistance reversal activity, the reversal times of the compounds are all higher than that of a positive control drug verapamil, and in addition, the compounds 2, 6,7, 8 and 9 have certain multidrug resistance reversal activity when being combined with an antitumor drug adriamycin. These compounds can be used as multidrug resistance reversal agents to assist in tumor chemotherapy.

Claims (3)

1. A pseudo-elenane diterpene derivative is characterized in that the structural formula of the compound is as follows:
Figure FDA0003118961370000011
Figure FDA0003118961370000021
wherein:
the name of structural formula 1 is: (2R,3R,4S,5R,7S,8S,9S,11S,12S,13S,14S,15R) -14-benzoyloxy-15-hydroxy-11, 12-epoxy-5, 7-diisobutyloxy-2, 3,8, 9-tetraacetoxy-pseudooliv-ine-6 (17) -ene;
the name of structural formula 2 is: (2R,3R,5S,7S,8S,9S,13S,14S) -14-benzoyloxy-5, 7-diisobutyloxy-2, 3,8, 9-tetraacetoxy-pseudoolivine-6 (17),4E, 11E-triene;
the name of structural formula 3 is: 14 β -benzoyloxy-2 α,7 β,8 α,9 α,15 β -pentahydroxy-5 α -isobutyryloxy-3 β -acetoxy-pseudoolivine-6 (17), 11E-diene;
the name of structural formula 4 is: 14 β -benzoyloxy-2 α,9 α,15 β -trihydroxy-5 α -isobutyryloxy-3 β,7 β,8 α -triacetoxy-pseudoolivine-6 (17), 11E-diene;
the name of structural formula 5 is: 14 beta-benzoyloxy-2 alpha, 8 alpha, 9 alpha, 15 beta, 17-pentahydroxy-5 alpha-isobutyryloxy-3 beta-triacetoxy-6, 7 epoxy-pseudoelemene-11E-ene;
the name of structural formula 6 is: 14 β -benzoyloxy-2 α,7 β,9 α,15 β -tetrahydroxy-5 α -isobutyryloxy-3 β -acetoxy-8 α -3' -methyl-benzoyloxy-pseudoolivine-6 (17), 11E-diene;
the name of structural formula 7 is: 14 β -benzoyloxy-2 α,8 α,9 α,15 β -tetrahydroxy-5 α -isobutyryloxy-3 β -acetoxy-7 β -3' -methylbenzoyloxy-pseudoolivine-6 (17), 11E-diene;
the name of structural formula 8 is: 14 β -benzoyloxy-2 α,15 β -dihydroxy-5 α -isobutyryloxy-3 β,7 β,8 α,9 α -tetraacetoxy-pseudoolivine-6 (17), 11E-diene;
the name of structural formula 9 is: 14 β -benzoyloxy-15 β -hydroxy-5 α -isobutyryloxy-2 α,3 β,7 β,8 α,9 α -pentaacetoxy-pseudoolivine-6 (17), 11E-diene;
the name of structural formula 10 is: 14 β -benzoyloxy-15 β -hydroxy-5 α -isobutyryloxy-3 β,7 β,8 α,9 α -tetraacetoxy-2 α -3' -methyl-benzoyloxy-pseudoolivine-6 (17), 11E-diene;
the name of structural formula 11 is: 14 β -benzoyloxy-15 β -hydroxy-5 α -isobutyryloxy-3 β,7 β,8 α,9 α -tetraacetoxy-2 α -isonicotinyloxy-pseudoCanane-6 (17), 11E-diene;
the name of structural formula 12 is: 14 β -benzoyloxy-15 β -hydroxy-5 α -isobutyryloxy-3 β,7 β,8 α,9 α -tetraacetoxy-2 α -pivaloyloxy-pseudoolivine-6 (17), 11E-diene;
the name of structural formula 13 is: 14 β -benzoyloxy-2 α,7 β,9 α,15 β -tetrahydroxy-5 α -isobutyryloxy-3 β -acetoxy-8 α -pivaloyloxy-pseudoolivine-6 (17), 11E-diene;
the name of structural formula 14 is: 14 β -benzoyloxy-2 α,15 β -dihydroxy-5 α -isobutyryloxy-3 β,7 β,9 α -triacetoxy-8 α -3' -methyl-benzoyloxy-pseudoolivine-6 (17), 11E-diene;
the name of structural formula 15 is: 14 β -benzoyloxy-15 β -hydroxy-5 α -isobutyryloxy-2 α,3 β,7 β,9 α -tetraacetoxy-8 α -3' -methyl-benzoyloxy-pseudoolivine-6 (17), 11E-diene;
the name of structural formula 16 is: 14 β -benzoyloxy-2 α,15 β -dihydroxy-5 α -isobutyryloxy-3 β,7 β,9 α -triacetoxy-8 α -pivaloyloxy-pseudoolivine-6 (17), 11E-diene;
the name of structural formula 17 is: 14 beta-benzoyloxy-15 beta-hydroxy-5 alpha-isobutyryloxy-2 alpha, 3 beta, 7 beta, 9 alpha-tetraacetoxy-8 alpha-pivaloyloxy-pseudoolivine-6 (17), 11E-diene.
2. The method for preparing the diterpene derivatives of the pseudoolivine type as claimed in claim 1, wherein the method comprises the following steps of using the active ingredient of Euphorbia pekinensis, formula ES3 as raw material:
a. dissolving a compound 14 beta-benzoyloxy-15 beta-hydroxy-5 alpha, 7 beta-diisobutyloxy-2 alpha, 3 beta, 8 alpha, 9 alpha-tetraacetoxy-pseudoleucomelane-6 (17), 11E-diene in dichloromethane, adding 2 times of m-chloroperoxybenzoic acid, stirring at room temperature for 6 days, quenching saturated sodium thiosulfate, extracting with ethyl acetate, washing with saturated sodium bicarbonate, water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating ethyl acetate, performing silica gel column 200-mesh gradient elution with 300 meshes, eluting with petroleum ether and ethyl acetate in a volume ratio of 3:1 to obtain a white solid compound 1 of (2R,3R,4S,5R,7S,8S,9S,11S,12S,13S,14S,15R) -14-benzoyloxy-15-hydroxy-11, 12-epoxy-5, 7-diisobutyloxy-2, 3,8, 9-tetraacetoxy-pseudoolivine-6 (17) -ene;
or dissolving a compound 14 beta-benzoyloxy-15 beta-hydroxy-5 alpha, 7 beta-diisobutyloxy-2 alpha, 3 beta, 8 alpha, 9 alpha-tetraacetoxy-pseudo-white-elenane-6 (17), 11E-diene in toluene, adding 10 times of thionyl chloride, protecting nitrogen, heating to 70 ℃, stirring for reaction for 1 hour, adding saturated sodium bicarbonate for quenching, extracting ethyl acetate, washing with water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating the ethyl acetate, performing gradient elution with a silica gel column of 200 meshes and 300 meshes, wherein the eluent is petroleum ether and ethyl acetate with the volume ratio of 5:1, and the white solid compound 2 is (2R,3R,5S,7S,8S,9S,13S,14S) -14-benzoyloxy-5, 7-diisobutyloxy-2, 3,8, 9-tetraacetoxy-pseudoolivine-6 (17),4E, 11E-triene;
or dissolving a compound 14 beta-benzoyloxy-15 beta-hydroxy-5 alpha, 7 beta-diisobutyloxy-2 alpha, 3 beta, 8 alpha, 9 alpha-tetraacetoxy-pseudoCanane-6 (17), 11E-diene in methanol, adding 2 times of 1, 8-diazabicycloundecene-7-ene, stirring for 2.5 hours at room temperature, adding hydrochloric acid (1mmol/L) for quenching, extracting with ethyl acetate, washing with water, saturated sodium bicarbonate and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating ethyl acetate, performing gradient elution with a silica gel column of 200 meshes and 300 meshes, eluting with petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain a white solid compound 3 of 14 beta-benzoyloxy-2 alpha, 7 beta, 8 alpha and 9 alpha, 15 β -pentahydroxy-5 α -isobutyryloxy-3 β -acetoxy-pseudoolivine-6 (17), 11E-diene;
b. dissolving the compound 3 obtained in the step a, namely 14 beta-benzoyloxy-2 alpha, 7 beta, 8 alpha, 9 alpha, 15 beta-pentahydroxyl-5 alpha-isobutyryloxy-3 beta-acetoxyl-pseudo-white-elenane-6 (17), 11E-diene, in dichloromethane, adding triethylamine and 3 times of acetic anhydride, stirring at room temperature for 8-12 hours, adding saturated sodium bicarbonate for quenching, extracting with ethyl acetate, washing with water, saturated sodium bicarbonate and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating ethyl acetate, performing gradient elution with a silica gel column of 200 meshes to 300 meshes, wherein an eluent is petroleum ether and ethyl acetate with the volume ratio of 1.5:1, and obtaining a white solid compound 4, namely 14 beta-benzoyloxy-2 alpha, 9 alpha, 15 beta-trihydroxy-5 alpha-isobutyryloxy-3 beta, 7 β,8 α -triacetoxy-pseudoolivine-6 (17), 11E-diene;
or dissolving the compound 3 obtained in the step a into 14 beta-benzoyloxy-2 alpha, 7 beta, 8 alpha, 9 alpha, 15 beta-pentahydroxy-5 alpha-isobutyryloxy-3 beta-acetoxyl-pseudo-white-elenane-6 (17), 11E-diene into dichloromethane, adding 1.5 times of m-chloroperoxybenzoic acid, stirring at room temperature for 24 hours, quenching with saturated sodium thiosulfate, extracting with ethyl acetate, washing with saturated sodium bicarbonate, water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating ethyl acetate, performing gradient elution with a silica gel column of 200 meshes to 300 meshes, eluting with petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain a white solid compound 5, namely 14 beta-benzoyloxy-2 alpha, 8 alpha, 9 alpha, 15 beta, 17-pentahydroxy-5 alpha-isobutyryloxy-3 beta-triacetoxy-6, 7 epoxy-pseudoolivine-11E-ene;
or dissolving the compound 314 beta-benzoyloxy-2 alpha, 7 beta, 8 alpha, 9 alpha, 15 beta-pentahydroxy-5 alpha-isobutyryloxy-3 beta-acetoxyl-pseudo-white olive-6 (17), 11E-diene obtained in the step a in pyridine, adding 2 times of 3-methylbenzoyl chloride, stirring at room temperature for 1 hour, adding saturated sodium bicarbonate to quench, extracting with ethyl acetate, washing with water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating the ethyl acetate, performing 200-mesh gradient elution through a silica gel column with 300 meshes, and eluting with petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain a white solid compound 6 of 14 beta-benzoyloxy-2 alpha, 7 beta, 9 alpha, 15 beta-tetrahydroxy-5 alpha-isobutyryloxy-3 beta-acetoxyl-8 alpha-3' -methyl-ethyl propionate Benzoyloxy-pseudoolivine-6 (17), 11E-diene;
or dissolving the compound 3 obtained in the step a, namely 14 beta-benzoyloxy-2 alpha, 7 beta, 8 alpha, 9 alpha, 15 beta-pentahydroxy-5 alpha-isobutyryloxy-3 beta-acetoxyl-pseudo-white-elenane-6 (17), 11E-diene, in dichloromethane, adding triethylamine, 5 times of acetic anhydride and a catalytic amount of 4-dimethylaminopyridine, stirring for 2 hours at room temperature, adding saturated sodium bicarbonate for quenching, extracting ethyl acetate, washing with water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating ethyl acetate, performing gradient elution with a silica gel column of 200 meshes and 300 meshes, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 1:1, and obtaining a white solid compound 8, namely 14 beta-benzoyloxy-2 alpha, 15 beta-dihydroxy-5 alpha-isobutyryloxy-3 beta, 7 β,8 α,9 α -tetraacetoxy-pseudoolivine-6 (17), 11E-diene;
or dissolving the compound 3 obtained in the step a, namely 14 beta-benzoyloxy-2 alpha, 7 beta, 8 alpha, 9 alpha, 15 beta-pentahydroxy-5 alpha-isobutyryloxy-3 beta-acetoxyl-pseudo-brumelane-6 (17), 11E-diene, into pyridine, adding 2 times of pivaloyl chloride, stirring at room temperature for 2 hours, adding saturated sodium bicarbonate for quenching, extracting ethyl acetate, washing with water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating the ethyl acetate, performing 200-mesh gradient elution through a silica gel column with 300 meshes, and eluting with petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain a white solid compound 13, namely 14 beta-benzoyloxy-2 alpha, 7 beta, 9 alpha, 15 beta-tetrahydroxy-5 alpha-isobutyryloxy-3 beta-acetoxyl-8 alpha-pivaloyloxy-pseudo-bruamane- 6, (17), 11E-diene;
c. standing the compound 6 obtained in the step b in methanol water solution for 7 days to obtain a white solid compound 7, wherein the compound 6 is 14 beta-benzoyloxy-2 alpha, 7 beta, 9 alpha, 15 beta-tetrahydroxy-5 alpha-isobutyryloxy-3 beta-acetoxyl-8 alpha-3 '-methyl-benzoyloxy-pseudo-brumiane-6 (17), the 11E-diene is subjected to concentration, gradient elution is carried out by a silica gel column with 200 meshes and 300 meshes, and eluents are petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain the white solid compound 7, the white solid compound 7 is 14 beta-benzoyloxy-2 alpha, 8 alpha, 9 alpha, 15 beta-tetrahydroxy-5 alpha-isobutyryloxy-3 beta-acetoxyl-7 beta-3' -methyl benzoyloxy-pseudo-brumiane-6 (17), 11E-diene;
or dissolving the compound 6 obtained in the step b into 14 beta-benzoyloxy-2 alpha, 7 beta, 9 alpha, 15 beta-tetrahydroxy-5 alpha-isobutyryloxy-3 beta-acetoxyl-8 alpha-3' -methyl-benzoyloxy-pseudo-white-elenane-6 (17), 11E-diene in dichloromethane, adding triethylamine, 5 times of acetic anhydride and a catalytic amount of 4-dimethylaminopyridine, stirring for 2 hours at room temperature, adding saturated sodium bicarbonate to quench, extracting with ethyl acetate, washing with water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating the ethyl acetate, performing gradient elution through a silica gel column with 200 meshes and 300 meshes, eluting with petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain a white solid compound 14 of 14 beta-benzoyloxy-2 alpha, 15 β -dihydroxy-5 α -isobutyryloxy-3 β,7 β,9 α -triacetoxy-8 α -3' -methyl-benzoyloxy-pseudoolivine-6 (17), 11E-diene;
or dissolving the compound 8 obtained in the step b into pyridine, adding 5 times of acetic anhydride and catalytic amount of 4-dimethylamino pyridine, refluxing and stirring for 24 hours, adding saturated sodium bicarbonate for quenching, extracting ethyl acetate, washing with water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating the ethyl acetate, performing gradient elution through a silica gel column with 200 meshes and 300 meshes, and eluting with petroleum ether and ethyl acetate in a volume ratio of 2:1 to obtain a white solid compound 9 of 14 beta-benzoyloxy-15 beta-hydroxy-5 alpha-isobutyryloxy-2 alpha, 3 β,7 β,8 α,9 α -pentaacetoxy-pseudoolivine-6 (17), 11E-diene;
or dissolving the compound 8 obtained in the step b into pyridine, adding 3-methyl benzoyl chloride in an amount which is 3 times that of the 14 beta-benzoyloxy-2 alpha, 15 beta-dihydroxy-5 alpha-isobutyryloxy-3 beta, 7 beta, 8 alpha, 9 alpha-tetraacetoxy-pseudoCanane-6 (17), 11E-diene, refluxing and stirring for 24 hours, adding saturated sodium bicarbonate for quenching, extracting with ethyl acetate, washing with water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating the ethyl acetate, performing gradient elution with a silica gel column of 200 meshes and 300 meshes, and eluting with petroleum ether and ethyl acetate in a volume ratio of 2:1 to obtain a white solid compound 10 of 14 beta-benzoyloxy-15 beta-hydroxy-5 alpha-isobutyryloxy-3 beta, 7 β,8 α,9 α -tetraacetoxy-2 α -3' -methyl-benzoyloxy-pseudoolivine-6 (17), 11E-diene;
or dissolving the compound 8 obtained in the step b into pyridine, adding 3 times of isonicotinoyl chloride and catalytic amount of 4-dimethylamino pyridine, refluxing and stirring for 4 hours, adding saturated sodium bicarbonate for quenching, extracting ethyl acetate, washing with water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating the ethyl acetate, performing gradient elution with a silica gel column of 200 meshes to 300 meshes, and eluting with petroleum ether and ethyl acetate in a volume ratio of 2:1 to obtain a white solid compound 11 of 14 beta-benzoyloxy-15 beta-hydroxy-5 alpha-isobutyryloxy-3 beta, 7 β,8 α,9 α -tetraacetoxy-2 α -isonicotinyloxy-pseudoCanane-6 (17), 11E-diene;
or dissolving the compound 8 obtained in the step b into pyridine, adding 2 times of pivaloyl chloride and 4-dimethylamino pyridine with pivaloyl chloride amount, refluxing and stirring for 18 hours, adding saturated sodium bicarbonate to quench, extracting with ethyl acetate, washing with water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating the ethyl acetate, performing gradient elution with a silica gel column of 200 meshes and 300 meshes, and eluting with petroleum ether and ethyl acetate in a volume ratio of 3:1 to obtain a white solid compound 12 of 14 beta-benzoyloxy-15 beta-hydroxy-5 alpha-isobutyryloxy-3 beta, 7 β,8 α,9 α -tetraacetoxy-2 α -pivaloyloxy-pseudoCanane-6 (17), 11E-diene;
d. dissolving the compound 13 obtained in the step b into 14 beta-benzoyloxy-2 alpha, 7 beta, 9 alpha, 15 beta-tetrahydroxy-5 alpha-isobutyryloxy-3 beta-acetoxyl-8 alpha-pivaloyloxy-pseudowhite elenane-6 (17), 11E-diene into dichloromethane, adding triethylamine, 4 times of acetic anhydride and catalytic amount of 4-dimethylaminopyridine, stirring for 2 hours at room temperature, adding saturated sodium bicarbonate for quenching, extracting with ethyl acetate, washing with water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating the ethyl acetate, performing gradient elution with a silica gel column of 200 meshes and 300 meshes, and eluting with petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain a white solid compound 16 of 14 beta-benzoyloxy-2 alpha, 15 β -dihydroxy-5 α -isobutyryloxy-3 β,7 β,9 α -triacetoxy-8 α -pivaloyloxy-pseudoolivine-6 (17), 11E-diene;
e. dissolving the compound 14 obtained in the step c into pyridine, adding 5 times of acetic anhydride and catalytic amount of 4-dimethylamino pyridine, refluxing and stirring for 48 hours, adding saturated sodium bicarbonate to quench, extracting with ethyl acetate, washing with water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating the ethyl acetate, performing 200-mesh and 300-mesh gradient elution through a silica gel column, and eluting with petroleum ether and ethyl acetate in a volume ratio of 2:1 to obtain a white solid compound 15, namely 14 beta-benzoyloxy-15 beta-hydroxy-5 alpha-isobutyryloxy-2 alpha, 3 β,7 β,9 α -tetraacetoxy-8 α -3' -methyl-benzoyloxy-pseudoolivine-6 (17), 11E-diene;
f. dissolving the compound 16 obtained in the step d into 14 beta-benzoyloxy-2 alpha, 15 beta-dihydroxy-5 alpha-isobutyryloxy-3 beta, 7 beta, 9 alpha-triacetoxy-8 alpha-pivaloyloxy-pseudoCanane-6 (17), 11E-diene, adding 3 times of acetic anhydride and catalytic amount of 4-dimethylaminopyridine, refluxing and stirring for 48 hours, adding saturated sodium bicarbonate for quenching, extracting with ethyl acetate, washing with water and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, concentrating the ethyl acetate, performing gradient elution with a silica gel column of 200 meshes and 300 meshes, and eluting with petroleum ether and ethyl acetate in a volume ratio of 2:1 to obtain a white solid compound 17 of 14 beta-benzoyloxy-15 beta-hydroxy-5 alpha-isobutyryloxy-2 alpha, 3 β,7 β,9 α -tetraacetoxy-8 α -pivaloyloxy-pseudoCanane-6 (17), 11E-diene.
3. The diterpene derivatives of pseudoolivine type according to claim 1, wherein the compound 1, 2, 6,7, 8,9, 10, 11,12, 14, 15, 16 or 17 is used for the preparation of drugs with multidrug resistance reversal activity.
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