CN118324845A - Bufogargarizin B preparation method - Google Patents

Bufogargarizin B preparation method Download PDF

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CN118324845A
CN118324845A CN202310040068.1A CN202310040068A CN118324845A CN 118324845 A CN118324845 A CN 118324845A CN 202310040068 A CN202310040068 A CN 202310040068A CN 118324845 A CN118324845 A CN 118324845A
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compound
reaction
organic solvent
temperature
bufogargarizin
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钟李平
冯锐
王旌晶
李闯创
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Southern University of Science and Technology
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Southern University of Science and Technology
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Abstract

The invention provides a preparation method of bufogargarizin B, which comprises the following steps

Description

Bufogargarizin B preparation method
Technical Field
The invention relates to the field of organic chemical synthesis, in particular to a preparation method of bufogargarizin B.
Background
Natural product bufogargarizin B is a steroid extracted from the venom of Bufo siccus in China with anti-inflammatory and anticancer activities by professor She Wencai and its cooperatives in university of south China in 2010, and its chemical structure is shown as follows:
In clinic, the extract from Bufo siccus has antiinflammatory, anticancer and heart failure resisting effects, and the steroid natural product is the main active ingredient. bufogargarizin B has a rare [5-7-6-5] tetracyclic core skeleton, and 10 chiral centers, has a very high oxidation state, and thus results in very high synthesis difficulty and high synthesis value. Limited by natural sources, natural products bufogargarizin B are currently available in small quantities isolated from nature, making it difficult to conduct more intensive studies of biological activity.
At present bufogargarizin B has no report on the total synthesis method, and based on the report, the development of a bufogargarizin B synthesis method has important practical significance for bufogargarizin B development and further activity research.
Disclosure of Invention
Based on the method, the preparation method of bufogargarizin B is simple and efficient in process, and meanwhile, a foundation can be laid for structural modification of bufogargarizin B.
The invention is realized by the following technical scheme.
Compound 1Mixing lithium bis (trimethylsilyl) amide, triethylamine and a first organic solvent, carrying out enolization reaction, carrying out silylation reaction on the enolization reaction product and trimethylchlorosilane, and carrying out oxidation reaction on the silylation reaction product and palladium acetate in a second organic solvent to prepare a compound 2Oxidizing the compound 2, sodium hydroxide aqueous solution and hydrogen peroxide in a third organic solvent to prepare a compound 3
The compound 3 and samarium diiodide are subjected to ring opening reaction in a fourth organic solvent to prepare a compound 4
Mixing the compound 4, chloromethyl methyl ether, 4-dimethylaminopyridine, N-diisopropylethylamine and a fifth organic solvent for hydroxyl protection reaction to prepare a compound 5
The compound 5 and 1, 8-diazo hetero double spiro [5.4.0] undec-7-alkene are subjected to series reaction of inverse aldol condensation and trans-cyclic aldol condensation in a sixth organic solvent to prepare a compound 6
The compound 6 and diisobutyl aluminum hydride are subjected to reduction reaction in a seventh organic solvent, and the product of the reduction reaction and tetrabutylammonium fluoride are subjected to desilication reaction to prepare a compound 7Oxidizing the compound 7, dess-martin oxidant, sodium bicarbonate and eighth organic solvent to prepare compound 8Mixing the compound 8, lithium bistrimethylsilylamino, triethylamine and a ninth organic solvent, carrying out enolization reaction, carrying out silicon-based reaction on the enolization reaction product and trimethylchlorosilane, carrying out oxidation reaction on the silicon-based reaction product and palladium acetate in the tenth organic solvent, and preparing the compound 9
The compound 9, N-diisopropylethylamine and silica gel are mixed with an eleventh organic solvent to carry out double bond shift reaction to prepare a compound 10
Mixing the compound 10, triphenylphosphine, manganese diacetylacetonate, phenylsilane and a twelfth organic solvent in an oxygen atmosphere, carrying out hydration reaction, mixing a hydration reaction product, trimethylsilicon imidazole and tetrabutylammonium fluoride, and carrying out a silicon-based reaction to prepare a compound 11
The compound 11, the lithium bistrimethylsilylamino and Comins reagent are mixed with thirteenth organic solvent to carry out triflate esterification reaction to prepare compound 12
The compound 12,Mixing with catalyst, and performing Suzuki coupling reaction in fourteenth organic solvent to obtain compound 13
The compound 13 and m-chloroperoxybenzoic acid are subjected to epoxidation reaction in a fifteenth organic solvent, and the product of the epoxidation reaction and borane dimethyl sulfide are subjected to reduction, double bond migration and ring-opening oxygen tandem reaction to prepare a compound 14
The compound 14, the dess-martin oxidant, the sodium bicarbonate and the sixteenth organic solvent are mixed for oxidation reaction to prepare a compound 15
Subjecting the compound 15 and 1, 8-diazabicyclo [5.4.0] undec-7-ene to elimination reaction in seventeenth organic solvent, and subjecting the product of elimination reaction and lithium bis (trimethylsilyl) amide to isomerization reaction to prepare a compound 16
The compound 16, (R) -2-methyl-CBS-oxazoloborane, borane dimethyl sulfide and eighteenth organic solvent are mixed for reduction reaction, and the product of the reduction reaction, 4-dimethylaminopyridine, triethylamine and acetic anhydride are mixed for acetylation reaction, thus preparing the compound 17
Under argon atmosphere, the compound 17, sodium hydroxide and N-bromosuccinimide are subjected to epoxidation reaction in a nineteenth organic solvent, a product of the epoxidation reaction is subjected to desilication reaction with tetrabutylammonium fluoride, the product of the desilication reaction, pyridine dichromate and acetic anhydride are mixed, oxidation reaction is carried out, the product of the oxidation reaction and lithium tetrafluoroborate are subjected to deprotection reaction in a twentieth organic solvent, and bufogargarizin B is prepared, wherein the structural formula of bufogargarizin B is shown as follows:
In one embodiment, one or more of the following conditions are met during the preparation of the compound 4 from the compound 3:
(1) The molar ratio of the compound 3 to the samarium diiodide is 1 (2.3-2.7);
(2) The ring-opening reaction temperature is-78 ℃ + -5 ℃.
In one embodiment, one or more of the following conditions are met during the preparation of the compound 6 from the compound 5:
(1) The mol ratio of the compound 5 to the 1, 8-diazabicyclo [5.4.0] undec-7-ene is 1 (14-16);
(2) The temperature of the tandem reaction of the inverse aldol condensation and the trans-cyclic aldol condensation is 66 ℃ +/-5 ℃.
In one embodiment, one or more of the following conditions are met during the preparation of the compound 9 from the compound 8:
(1) The molar ratio of the compound 8 to the lithium bis (trimethylsilyl) amide to the triethylamine to the trimethylchlorosilane to the palladium acetate is 1 (4.5-5.5), 18-22 (4.5-5.5) and 0.8-1.2;
(2) The enolization reaction temperature is-78+/-5 ℃;
(3) The temperature of the silicon-based reaction is-78+/-5 ℃;
(4) The temperature of the oxidation reaction was 25 ℃ + -5 ℃.
In one embodiment, one or more of the following conditions are met during the preparation of the compound 10 from the compound 9:
(1) The mol ratio of the compound 9 to the N, N-diisopropylethylamine to the silica gel is 1 (50-60) (70-80);
(2) The temperature of the double bond shift reaction is 15-30 ℃.
In one embodiment, one or more of the following conditions are met during the preparation of the compound 13 from the compound 12:
(1) The compound 12 and the The molar ratio of (1) to (1.4);
(2) The temperature of the suzuki coupling reaction is 60+/-5 ℃.
In one embodiment, one or more of the following conditions are met during the preparation of the compound 14 from the compound 13:
(1) The molar ratio of the compound 13, the m-chloroperoxybenzoic acid and the borane dimethyl sulfide is 1 (1-1.4) (1.3-1.7);
(2) The temperature of the epoxidation reaction is 25+/-5 ℃;
(3) The temperature of the serial reaction of reduction, double bond migration and ring opening oxygen is 0+/-5 ℃.
In one embodiment, one or more of the following conditions are met during the preparation of the compound 15 from the compound 14:
(1) The molar ratio of the compound 14, the dess-martin oxidant and the sodium bicarbonate is 1 (1-1.4): 2.3-2.7);
(2) The temperature of the oxidation reaction was 25 ℃ + -5 ℃.
In one embodiment, one or more of the following conditions are met during the preparation of the compound 16 from the compound 15:
(1) The molar ratio of the compound 15, the 1, 8-diazabicyclo [5.4.0] undec-7-ene and the lithium bistrimethylsilyl amide is 1 (1.8-2.2): 4.5-5.5);
(2) The temperature of the elimination reaction is 25+/-5 ℃;
(3) The temperature of the isomerization reaction was-98 ℃ + -5 ℃.
In one embodiment, one or more of the following conditions are met during the preparation of bufogargarizin B from the compound 17:
(1) The molar ratio of the compound 17, the sodium hydroxide, the N-bromosuccinimide, the tetrabutylammonium fluoride, the pyridine dichromate, the acetic anhydride and the lithium tetrafluoroborate is 1 (3.8-4.2), 1-1.4, 3.8-4.2, 1.3-1.7 and 4.5-5.5;
(2) The temperature of the epoxidation reaction is 25+/-5 ℃;
(3) The desilication reaction temperature is 25+/-5 ℃;
(4) The temperature of the oxidation reaction is 15-30 ℃;
(5) The temperature of the deprotection reaction was 82 ℃ + -5 ℃.
Compared with the prior art, the preparation method of bufogargarizin B has the following beneficial effects:
the invention uses The full synthesis method of the natural product bufogargarizin B is provided for the initial material, the preparation process is simple and efficient, the yield is high, the byproducts are few, the obtained amount of bufogargarizin B can be greatly increased, and therefore, the bufogargarizin B can be subjected to more intensive biological activity research. In addition, the preparation method of bufogargarizin B is easier to modify the structure, so that sufficient material basis can be provided for screening lead compounds in future biological activity research and new drug development, and further contribution is made to the research direction of anti-inflammatory, anti-tumor and other important human diseases.
Detailed Description
In order that the invention may be readily understood, a more particular description of the invention will be rendered by reference to specific embodiments that are illustrated in the appended drawings. Preferred embodiments of the present invention are shown in the examples. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items.
The invention provides a preparation method of bufogargarizin B, which comprises the following steps:
Compound 1 Mixing lithium bis (trimethylsilyl) amide, triethylamine and a first organic solvent, carrying out enolization reaction, carrying out silylation reaction on the enolization reaction product and trimethylchlorosilane, and carrying out oxidation reaction on the silylation reaction product and palladium acetate in a second organic solvent to prepare a compound 2Oxidizing the compound 2, sodium hydroxide aqueous solution and hydrogen peroxide in a third organic solvent to prepare a compound 3
Ring-opening reaction of compound 3 and samarium diiodide in fourth organic solvent to prepare compound 4
Mixing the compound 4, chloromethyl methyl ether, 4-dimethylaminopyridine, N-diisopropylethylamine and a fifth organic solvent for hydroxyl protection reaction to prepare a compound 5
Compound 5 and 1, 8-diazo hetero double spiro [5.4.0] undec-7-ene are subjected to series reaction of inverse aldol condensation and trans-cyclic aldol condensation in a sixth organic solvent to prepare compound 6
The compound 6 and diisobutyl aluminum hydride are subjected to reduction reaction in a seventh organic solvent, and the product of the reduction reaction and tetrabutylammonium fluoride are subjected to desilication reaction to prepare the compound 7Oxidizing the compound 7, the dess-martin oxidant, sodium bicarbonate and an eighth organic solvent to prepare a compound 8Mixing the compound 8, lithium bis (trimethylsilyl) amide, triethylamine and a ninth organic solvent, carrying out enolization reaction, carrying out silylation reaction on the enolization reaction product and trimethylchlorosilane, and carrying out oxidation reaction on the silylation reaction product and palladium acetate in the tenth organic solvent to prepare the compound 9
Mixing the compound 9, N-diisopropylethylamine, silica gel and eleventh organic solvent, and performing double bond shift reaction to prepare a compound 10
Mixing compound 10, triphenylphosphine, manganese diacetylacetonate, phenylsilane and twelfth organic solvent in an oxygen atmosphere, carrying out hydration reaction, mixing the hydration reaction product, trimethylsilicon imidazole and tetrabutylammonium fluoride, and carrying out silicon-based reaction to prepare compound 11
Compound 11, lithium bistrimethyl silicon amide and Comins reagent are mixed with thirteenth organic solvent to carry out triflate esterification reaction to prepare compound 12
Compound 12,Mixing with catalyst, and performing Suzuki coupling reaction in fourteenth organic solvent to obtain compound 13
The compound 13 and m-chloroperoxybenzoic acid are subjected to epoxidation reaction in a fifteenth organic solvent, and the product of the epoxidation reaction and borane dimethyl sulfide are subjected to reduction, double bond migration and ring-opening oxygen tandem reaction to prepare a compound 14
Compound 14, dess-Martin oxidant, sodium bicarbonate and sixteenth organic solvent are mixed for oxidation reaction to prepare compound 15
The compound 15 and 1, 8-diazo hetero double spiro [5.4.0] undec-7-ene are subjected to elimination reaction in seventeenth organic solvent, and the product of elimination reaction and lithium bistrimethylsilyl amide are subjected to isomerization reaction to prepare the compound 16
Mixing compound 16, (R) -2-methyl-CBS-oxazoloborane, borane dimethyl sulfide and eighteenth organic solvent, carrying out reduction reaction, mixing the product of the reduction reaction, 4-dimethylaminopyridine, triethylamine and acetic anhydride, carrying out acetylation reaction, preparing compound 17
Under argon atmosphere, performing epoxidation reaction on a compound 17, sodium hydroxide and N-bromosuccinimide in a nineteenth organic solvent, performing desilication reaction on a product of the epoxidation reaction and tetrabutylammonium fluoride, mixing the product of the desilication reaction, pyridine dichromate and acetic anhydride, performing oxidation reaction, and performing deprotection reaction on the product of the oxidation reaction and lithium tetrafluoroborate in the twentieth organic solvent to prepare bufogargarizin B and bufogargarizin B with the structural formula shown as follows:
in a specific example, one or more of the following conditions are met during the preparation of compound 2 from compound 1:
(1) The molar ratio of the compound 1 to the lithium bistrimethylsilyl amide to the triethylamine to the trimethylchlorosilane to the palladium acetate is 1 (2.3-2.7), 18-22, 1.8-2.2 and 1.8-2.2;
(2) The enolization reaction temperature is-78+/-5 ℃;
(3) The temperature of the silicon-based reaction is-78+/-5 ℃;
(4) The temperature of the oxidation reaction was 25 ℃ + -5 ℃.
In a specific example, one or more of the following conditions are met during the preparation of compound 3 from compound 2:
(1) The mol ratio of the compound 2 to the sodium hydroxide aqueous solution is 1 (1.8-2.2);
(2) The temperature of the oxidation reaction was 66 ℃ + -5 ℃.
In a specific example, one or more of the following conditions are met during the preparation of compound 4 from compound 3:
(1) The mol ratio of the compound 3 to the samarium diiodide is 1 (2.3-2.7);
(2) The ring-opening reaction temperature is-78 ℃ + -5 ℃.
In a specific example, one or more of the following conditions are met during the preparation of compound 5 from compound 4:
(1) The mol ratio of the compound 4, chloromethyl methyl ether, 4-dimethylaminopyridine and N, N-diisopropylethylamine is 1 (1.8-2.2): (0.1-0.3): (9-11);
(2) The temperature of the hydroxyl protection reaction is 15-30 ℃.
In a specific example, one or more of the following conditions are met during the preparation of compound 6 from compound 5:
(1) The mol ratio of the compound 5 to the 1, 8-diazabicyclo [5.4.0] undec-7-ene is 1 (14-16);
(2) The temperature of the tandem reaction of the inverse aldol condensation and the trans-cyclic aldol condensation is 66 ℃ +/-5 ℃.
In a specific example, one or more of the following conditions are met during the preparation of compound 7 from compound 6:
(1) The mol ratio of the compound 6, the diisobutyl aluminum hydride and the tetrabutylammonium fluoride is 1 (1.8-2.2) to 3.8-4.2;
(2) The temperature of the reduction reaction is-78+/-5 ℃;
(3) The temperature of the desilication reaction was 66 ℃ + -5 ℃.
In a specific example, one or more of the following conditions are met during the preparation of compound 8 from compound 7:
(1) The mol ratio of the compound 7, the dess-martin oxidant and the sodium bicarbonate is 1 (1-1.4): 2.8-3.2);
(2) The temperature of the oxidation reaction was 25 ℃ + -5 ℃.
In a specific example, one or more of the following conditions are met during the preparation of compound 9 from compound 8:
(1) The mol ratio of the compound 8 to the lithium bistrimethylsilyl amide to the triethylamine to the trimethylchlorosilane to the palladium acetate is 1 (4.5-5.5), 18-22, 4.5-5.5 and 0.8-1.2;
(2) The enolization reaction temperature is-78+/-5 ℃;
(3) The temperature of the silicon-based reaction is-78+/-5 ℃;
(4) The temperature of the oxidation reaction was 25 ℃ + -5 ℃.
In a specific example, one or more of the following conditions are met during the preparation of compound 10 from compound 9:
(1) The mol ratio of the compound 9, N-diisopropylethylamine to the silica gel is 1 (50-60) (70-80);
(2) The temperature of the double bond shift reaction is 15-30 ℃.
In one specific example, one or more of the following conditions are met during the preparation of compound 11 from compound 10:
(1) The mol ratio of the compound 10, triphenylphosphine, manganese diacetylacetonate, phenylsilane, trimethylsilicon imidazole and tetrabutylammonium fluoride is 1 (1.3-1.7): (3.8-4.2): (2.8-3.2): (9-11): (0.08-0.12);
(2) The temperature of the hydration reaction is 25+/-5 ℃;
(3) The temperature of the silylation reaction was 60 ℃ + -5 ℃.
In one specific example, one or more of the following conditions are met during the preparation of compound 12 from compound 11:
(1) The mol ratio of the compound 11 to the lithium bis (trimethylsilyl) amide to Comins reagent is 1 (1.3-1.7);
(2) The triflate esterification reaction comprises the following steps: mixing the compound 11, the lithium bis (trimethylsilyl) amide and the thirteenth organic solvent at the temperature of minus 78+/-5 ℃, then adding Comins reagent, mixing at the temperature of minus 78+/-5 ℃, and continuing mixing at the temperature of 25+/-5 ℃.
In one specific example, one or more of the following conditions are met during the preparation of compound 13 from compound 12:
(1) Compound 12 The molar ratio of (1) to (1.4);
(2) The temperature of the suzuki coupling reaction is 60+/-5 ℃.
In one specific example, one or more of the following conditions are met during the preparation of compound 14 from compound 13:
(1) The mol ratio of the compound 13, the m-chloroperoxybenzoic acid and the borane dimethyl sulfide is 1 (1-1.4): 1.3-1.7);
(2) The temperature of the epoxidation reaction is 25+/-5 ℃;
(3) The temperature of the serial reaction of reduction, double bond migration and ring opening oxygen is 0+/-5 ℃.
In one specific example, one or more of the following conditions are met during the preparation of compound 15 from compound 14:
(1) The mol ratio of the compound 14, the dess-martin oxidant and the sodium bicarbonate is 1 (1-1.4): 2.3-2.7);
(2) The temperature of the oxidation reaction was 25 ℃ + -5 ℃.
In one specific example, one or more of the following conditions are met during the preparation of compound 16 from compound 15:
(1) The mol ratio of the compound 15, 1, 8-diazabicyclo [5.4.0] undec-7-ene to the lithium bistrimethylsilyl amide is 1 (1.8-2.2): 4.5-5.5;
(2) The temperature of the elimination reaction is 25+/-5 ℃;
(3) The temperature of the isomerization reaction was-98 ℃ + -5 ℃.
In one specific example, one or more of the following conditions are met during the preparation of compound 17 from compound 16:
(1) The molar ratio of the compound 16, (R) -2-methyl-CBS-oxazoleboronic acid, borane dimethyl sulfide, 4-dimethylaminopyridine, triethylamine and acetic anhydride is1 (1.8-2.2): (0.2-0.4): (9-11): (4.5-5.5);
(2) The temperature of the reduction reaction is 25+/-5 ℃;
(3) The temperature of the acetylation reaction was 25 ℃ + -5 ℃.
In one specific example, one or more of the following conditions are met during preparation bufogargarizin B from compound 17:
(1) The molar ratio of the compound 17, sodium hydroxide, N-bromosuccinimide, tetrabutylammonium fluoride, pyridine dichromate, acetic anhydride and lithium tetrafluoroborate is 1 (3.8-4.2), 1-1.4, 3.8-4.2, 1.3-1.7 and 4.5-5.5;
(2) The temperature of the epoxidation reaction is 25+/-5 ℃;
(3) The desilication reaction temperature is 25+/-5 ℃;
(4) The temperature of the oxidation reaction is 15-30 ℃;
(5) The temperature of the deprotection reaction was 82 ℃ + -5 ℃.
In a specific example, the preparation of compound 1 comprises the steps of:
Compound 18 Carrying out reduction reaction with diisobutyl aluminum hydride in a twenty-first organic solvent, and carrying out hydroxyl protection reaction on the product of the reduction reaction, tertiary butyl dimethyl chlorosilane and alkali in the twenty-second organic solvent to prepare a compound 19Ring-opening reaction of compound 19 and lithium aluminum hydride in twenty-third organic solvent, and oxidation reaction of ring-opening reaction product, oxalyl chloride, dimethyl sulfoxide and triethylamine in twenty-fourth organic solvent to obtain compound 20
Nucleophilic addition reaction of compound 20 and cyclopropyl magnesium bromide in twenty-fifth organic solvent, mixing nucleophilic addition reaction product, triethyl silicon-based trifluoro methane sulfonate and N, N-diisopropylethylamine, and silicon-based reaction to prepare compound 21
Compound 21, p-toluenesulfonyl methyl isonitrile, potassium tert-butoxide and a twenty-sixth organic solvent are mixed and subjected to Fan Lesen reaction to prepare compound 22Compound 22 and diisobutyl aluminum hydride are subjected to reduction reaction in a twenty-seventh organic solvent, and then the product of the reduction reaction and sodium methoxide are subjected to isomerization reaction in a twenty-eighth organic solvent to prepare compound 23
Compound 23, dimethyl (1-diazo-2-oxopropyl) phosphonateCarrying out Seyferth-Gilbert carburetion reaction with potassium carbonate in twenty-eighth organic solvent, and then carrying out desilication reaction on Seyferth-Gilbert carburetion reaction product and tetrabutylammonium fluoride to prepare compound 24
Compound 24, dess-martin oxidant, sodium bicarbonate and twenty-ninth organic solvent are mixed to perform oxidation reaction to prepare compound 25
Compound 25, trimethylsilyl triflate and diisopropylethylamine are subjected to a silylation reaction in a thirty-first organic solvent to prepare compound 26Cycloaddition of Compound 26 in thirty-first organic solvent under the catalysis of ruthenium Tri (acetonitrile) cyclopentadienyl hexafluorophosphate to prepare Compound 27
In the oxygen atmosphere, compound 27, triphenylphosphine, manganese acetylacetonate, phenylsilane and thirty-second organic solvent are mixed for hydration reaction to prepare compound 1
In one specific example, one or more of the following conditions are met during the preparation of compound 19 from compound 18:
(1) The mol ratio of the compound 18, diisobutyl aluminum hydride and tertiary butyl dimethyl chlorosilane is 1 (0.8-1.2) to 1.3-1.7;
(2) The temperature of the reduction reaction is-78+/-5 ℃;
(3) The base is selected from imidazole or triethylamine;
(4) The temperature of the hydroxyl protection reaction is 15-30 ℃.
In one specific example, one or more of the following conditions are met during the preparation of compound 20 from compound 19:
(1) The molar ratio of the compound 19 to the lithium aluminum hydride is 1 (1-1.4);
(2) The temperature of the ring-opening reaction is 0+/-5 ℃;
(3) The oxidation reaction comprises the following steps: mixing the ring-opening reaction product, oxalyl chloride, dimethyl sulfoxide and a fourth organic solvent at the temperature of minus 78+/-5 ℃, adding triethylamine, and heating to 15-30 ℃.
In one specific example, one or more of the following conditions are met during the preparation of compound 21 from compound 20:
(1) The mol ratio of the compound 20, the cyclopropyl magnesium bromide, the triethyl silicon-based trifluoro methane sulfonate and the N, N-diisopropylethylamine is 1 (0.8-1.2): 2.8-3.2): 5.8-6.2);
(2) The temperature of nucleophilic addition reaction is-78+/-5 ℃;
(3) The temperature of the silicon-based reaction is 15-30 ℃.
In one specific example, one or more of the following conditions are met during the preparation of compound 22 from compound 21:
(1) The molar ratio of the compound 21, the p-toluenesulfonyl methyl isonitrile and the potassium tert-butoxide is 1 (1.8-2.2) (9-11);
(2) The Fan Lesen reaction includes the following steps: mixing compound 21, potassium tert-butoxide and a twenty-sixth organic solvent at 25 ℃ +/-5 ℃, then cooling to 0 ℃ +/-5 ℃, adding p-toluenesulfonyl methyl isonitrile, and then heating to 15-30 ℃.
In one specific example, one or more of the following conditions are met during the preparation of compound 23 from compound 22:
(1) The molar ratio of the compound 22 to the diisobutyl aluminum hydride is 1 (2.3-2.7);
(2) The temperature of the reduction reaction was-78 ℃ + -5 ℃.
In one specific example, one or more of the following conditions are met during the preparation of compound 24 from compound 23:
(1) The molar ratio of the compound 23, the dimethyl (1-diazo-2-oxopropyl) phosphonate to the tetrabutylammonium fluoride is 1 (1.3-1.7): 1.8-2.2);
(2) Seyferth-Gilbert carburising reaction temperature is 25+/-5 ℃;
(3) The temperature of the desilication reaction was 25 ℃ + -5 ℃.
In one specific example, one or more of the following conditions are met during the preparation of compound 25 from compound 24:
(1) The mol ratio of the compound 24, the dess-martin oxidant and the sodium bicarbonate is 1 (1-1.4): 2.8-3.2);
(2) The temperature of the oxidation reaction was 25 ℃ + -5 ℃.
In one specific example, one or more of the following conditions are met during the preparation of compound 26 from compound 25:
(1) The mol ratio of the compound 25, the trimethylsilyl triflate and the diisopropylethylamine is 1 (1.3-1.7) to 4.5-5.5;
(2) The temperature of the enol silicon etherification reaction is 25+/-5 ℃.
In one specific example, one or more of the following conditions are met during the preparation of compound 27 from compound 26:
(1) The temperature of the [5+2] cycloaddition reaction is 55+/-5 ℃;
(2) The time of the [5+2] cycloaddition reaction is 12 h.+ -. 2h.
In one specific example, one or more of the following conditions are met during the preparation of compound 1 from compound 27:
(1) The mol ratio of the compound 27, triphenylphosphine, manganese acetylacetonate and phenylsilane is 1 (1.3-1.7): (1.8-2.2);
(2) The temperature of the hydration reaction was 25 ℃ + -5 ℃.
The preparation method of bufogargarizin B of the present invention is described in further detail below with reference to specific examples. The raw materials used in the following examples are all commercially available products unless otherwise specified. The reaction charge ratio in the present invention is often expressed as a weight-to-volume ratio, which refers to the ratio of the weight of the reaction raw material to the weight or volume of the reaction reagent unless otherwise specified.
Example 1
The embodiment provides a preparation method of bufogargarizin B, which specifically comprises the following steps:
Synthesis of Compound 1
Compound 18 (25.0 g,112.5mmol,1.0 equiv.) is dissolved in tetrahydrofuran (400 mL) and DIBAL (1.5 mol per liter of toluene solution, 75.0mL,112mmol,1.0 equiv.) is added dropwise at-78deg.C, after which it is stirred at this temperature for one hour. Then, copper tartrate (36.1 g,168mmol,1.5 equiv.) was added at this temperature, after which the reaction was allowed to warm to room temperature and stirring continued for one hour. Imidazole (23.0 g,338mmol,3.0 equiv.) and TBSCl (25.5 g,169mmol,1.5 equiv.) were then added and stirred for 12 hours. Saturated aqueous sodium bicarbonate (200 mL) was added, extracted with ethyl acetate (200 mL. Times.3), and the combined organic phases were washed once with saturated brine (200 mL), dried over Na 2SO4, and filtered to give a crude product concentrated. The crude product was purified by column chromatography on silica gel (hexane:EtOAc 10:1→4:1) to give compound 19 (33.1 g, 87% yield) as a colorless oily product.
Compound 19 (33.1 g,97.9mmol,1.0 equiv.) is dissolved in tetrahydrofuran (400 mL) and lithium aluminum hydride (4.44 g,117mmol,1.2 equiv.) is added dropwise at 0deg.C, after which it is stirred for twenty minutes at this temperature. Water (4.4 mL and NaOH (2.0M aq.,4.4 mL) were then added and stirred, the solids were removed by filtration, the resulting organic phase was spin-dried and the crude product obtained was directly put into the next step.
DMSO was dissolved in DCM and oxalyl chloride was added at-78 ℃ and stirred for 30 min. The crude S1 obtained above was dissolved in DCM, slowly added to the reaction and stirred at this temperature for one hour. Subsequently, triethylamine was added and the mixture was warmed to room temperature. The reaction was quenched with sodium bicarbonate, extracted with ethyl acetate, dried over sodium sulfate, filtered, and the resulting organic phase was dried by spinning to a concentrated crude product. The crude product was purified by column chromatography on silica gel (hexane:EtOAc 10:1→5:1) to give compound 20 (27.5 g, 83% yield) as a colourless oil.
Rf＝0.6(hexane/ethyl acetate＝10/1)；
(c＝0.1in MeOH)；
1H NMR(400MHz,CDCl3)δ9.68(s,1H),3.57(t,J＝8.3Hz,1H),2.59–2.47(m,1H),2.47–2.24(m,3H),2.28–2.18(m,1H),1.94–1.81(m,2H),1.64(d,J＝5.4Hz,2H),1.62–1.47(m,2H),1.43(d,J＝11.3Hz,2H),1.35(m,1H)0.99–0.94(m,3H),0.82(s,9H),-0.05(s,6H);
13C NMR(100MHz,CDCl3)δ212.2,202.2,80.1,49.6,49.2,43.4,41.7,37.8,35.6,31.3,25.6,23.9,18.8,17.8,10.7,-4.7,-5.1;
HRMS (ESI) C 19H35O3Si[M+H]+ calculated molecular weight 339.2355; the molecular weight was found to be 339.2353.
Substrate compound 20 (10.0 g,29.5mmol,1.0 equiv.) was dissolved in dichloromethane (150 mL) and cyclopropylmagnesium bromide (0.5M in THF,59.0mL,29.5mmol,1.0equiv) was added dropwise at-78 ℃ and, after completion, stirred at this temperature for ten minutes. Then, at this temperature, azosin-diisopropylethylamine (30.8 ml,177mmol,6.0 equiv.) and triethylsilyl triflate (20.0 ml,88.5mmol,3.0 equiv.) were added, and after the addition was completed, the reaction was warmed to room temperature and stirred for two hours. Then quenched with saturated aqueous sodium bicarbonate (100 mL), extracted with ethyl acetate (100 ml×3), and the combined organic phases were dried by spinning to give the intermediate as a colourless oil (c9dr=1.5:1). The crude product obtained was dissolved in 1 mol per liter of sodium methoxide solution (100 mL), heated to 65 ℃ and stirred for 12 hours. The methanol was then removed by spin-off, extracted with ethyl acetate (100 mL. Times.3), washed once with saturated brine (200 mL), dried over Na 2SO4, and filtered to give a crude product in which the organic phase was concentrated. The crude product was purified by column chromatography on silica gel (hexane:etoac 20:1→10:1) to give compound 21 (dr=8:1, 9.05g, 62% yield) as a colourless oil.
Rf＝0.7(hexane/ethyl acetate＝4/1)；
(c＝0.1in MeOH)；
IR(film)λmax 2955,2930,2876,1714,1456,1082,837cm-1；
1H NMR(400MHz,CDCl3)(major)δ3.62(td,J＝8.4,3.3Hz,1H),3.06–2.91(m,1H),2.57–2.36(m,1H),2.34–2.21(m,2H),2.06–1.95(m,1H),1.91(m,1H),1.74–1.57(m,4H),1.55–1.47(m,4H),1.40(d,J＝5.4Hz,2H),1.01(d,J＝1.6Hz,3H),0.95(t,J＝7.9Hz,9H),0.88(s,9H),0.64–0.55(m,6H),0.51–0.40(m,2H),0.23(dd,J＝5.1,1.2Hz,1H),0.15(d,J＝5.1Hz,1H),0.01(d,J＝1.0Hz,6H);
13C NMR(100MHz,CDCl3)(major)δ212.9,80.5,77.2,50.9,49.7,43.6,38.1,36.1,35.9,31.6,25.8,24.3,22.8,18.1,17.7,11.0,7.0,5.3,3.7,2.5,-4.5,-4.9;
HRMS (ESI) C 28H54O2Si2[M+H]+ calculated molecular weight 495.3690; the molecular weight was found to be 495.3684.
Compound 21 (10 g,20.2mmol,1.0 equiv.) is dissolved in ethylene glycol dimethyl ether (210 mL) and slowly added to a potassium tert-butoxide solution (1.3M in t-BuOH,155mL,202mmol,10.0 equiv.) at 25℃and, after completion, stirred at this temperature for ten minutes. Then, the reaction was cooled to 0 ℃, a solution of p-toluenesulfonyl methyl isonitrile (0.202M in DME,200mL,40.4mmol,2.0equiv) was slowly added, and after the addition was completed, the reaction system was warmed to room temperature and stirred for two hours. Then, saturated aqueous ammonium chloride (80 mL) was added to quench, extraction was performed with ethyl acetate (100 ml×3), and the combined organic phases were washed once with saturated brine (200 mL), dried over Na 2SO4 and filtered to give crude compound 22 as concentrated organic phase. The crude product was used in the next step without further purification.
The crude compound 22 obtained above was dissolved in dichloromethane (100 mL) and diisobutylaluminum hydride (1.5M in toluene,29.7mL,44.6mmol,2.5equiv) was added dropwise at-78 ℃ and after completion, stirred at this temperature for two hours. Then, at this temperature, a saturated potassium sodium tartrate solution (100 mL) was added to quench, and the reaction system was warmed to room temperature and stirred for two hours. Subsequently, extracted with ethyl acetate (100 ml×3), the combined organic phases were washed once with saturated brine (200 mL), dried over Na 2SO4, and filtered to give a crude product in which the organic phase was concentrated. The crude product was purified by column chromatography on silica gel (hexane:EtOAc 20:1→15:1) to give compound 23 (7.52 g, 73% yield) as a colorless oily product.
Rf＝0.55(hexane/ethyl acetate＝4/1)；
1H NMR(500MHz,CD2Cl2)(major)δ9.69–9.30(m,1H),3.60(d,J＝1.1Hz,1H),3.17–2.80(m,1H),2.14–2.01(m,1H),1.90(s,1H),1.79(d,J＝12.4Hz,2H),1.66(d,J＝9.5Hz,2H),1.48–1.25(m,4H),1.11(m,3H),0.94(t,J＝7.9Hz,9H),0.88(s,9H),0.81(d,J＝8.0Hz,3H),0.76(s,4H),0.57(t,J＝7.9Hz,7H),0.49–0.22(m,2H),0.02(d,J＝2.5Hz,6H);
13C NMR(125MHz,CDCl3)(major)δ205.1,81.5,77.2,55.1,46.9,43.4,35.6,34.0,30.4,27.1,25.8,23.9,22.5,18.1,17.4,11.0,6.9,5.2,3.6,2.4,1.0,-4.5,-4.9;
HRMS (ESI) calculated molecular weight C 29H57O3Si2[M+H]+: 509.3846; the molecular weight was found to be 509.3847.
Compound 23 (7.56G, 14.7mmol,1.0 equiv.) is dissolved in methanol (80 mL) and potassium carbonate (6.09G, 44.1mmol,3.0 equiv.) and compound G (3.31 mL,22.05mmol,1.5 equiv.) are added at 0deg.C and, after completion, stirred at 25deg.C for two hours. Then, tetrabutylammonium fluoride (1.0M in THF,29.4mL,29.4mmol,2.0equiv.) was added and stirred at this temperature for half an hour. Then, saturated sodium bicarbonate solution (50 mL) was added, extracted with ethyl acetate (100 mL. Times.3), and the combined organic phases were washed once with saturated brine (200 mL), dried over Na 2SO4, and filtered to give a crude product in which the organic phase was concentrated. The crude product was purified by column chromatography on silica gel (hexane:EtOAc 20:1→10:1) to give compound 24 (3.97 g, 77% yield) as a colorless oil.
Rf＝0.45(hexane/ethyl acetate＝4/1)；
(c＝0.5in MeOH)；
IR(film)λmax 3310,2857,1456,1058,901,835cm-1；
1H NMR(500MHz,CDCl3)δ3.54(t,J＝8.3Hz,1H),2.84(dd,J＝8.9,3.8Hz,1H),2.06(dd,J＝5.1,2.3Hz,1H),2.04–1.96(m,1H),1.91–1.81(m,2H),1.74–1.66(m,3H),1.58(m,6H),1.46–1.39(m,1H),1.33(m,1H),1.05–0.93(m,2H),0.87(s,9H),0.74(s,3H),0.50(m,2H),0.25(m,2H),-0.01(d,J＝2.3Hz,6H);
13C NMR(125MHz,CDCl3)δ87.8,87.7,81.6,81.5,77.4,77.2,68.9,68.8,47.4,47.0,43.6,43.5,40.1,40.1,36.6,36.5,34.3,34.1,32.5,32.1,30.5,29.2,29.2,26.8,26.5,25.8,24.0,23.9,18.1,17.9,17.8,11.1,2.9,2.8,2.3,-4.5,-4.9;
HRMS (ESI) calculated molecular weight C 24H43O2Si[M+H]+: 391.3032; the molecular weight was found to be 391.3024.
Compound 24 (12.2 g,31.2mmol,1.0 equiv.) is dissolved in dichloromethane (150 mL) and sodium bicarbonate (7.86 g,93.6mmol,3.0 equiv.) and dess-martin oxidant (15.9 g,37.4mmol,1.2 equiv.) are added at 0 ℃ and after completion, stirred at 25 ℃ for two hours. Subsequently, a saturated sodium sulfite solution (50 mL) was added, extracted with ethyl acetate (100 ml×3), and the combined organic phases were washed once with saturated brine (200 mL), dried over Na 2SO4, and filtered to give a crude product in which the organic phase was concentrated. The crude product was purified by column chromatography on silica gel (hexane:EtOAc 20:1→10:1) to give compound 25 (10.8 g, 89% yield) as a colorless oil.
Rf＝0.65(hexane/ethyl acetate＝10/1)；
(c＝0.3in MeOH)；
IR(film)λmax 3310,2932,1697,1471,1115,901,627cm-1；
1H NMR(500MHz,CDCl3)δ3.54(t,J＝8.3Hz,1H),2.56(m,2H),2.08(s,1H),1.97–1.86(m,5H),1.78–1.67(m,3H),1.64–1.54(m,2H),1.35(dd,J＝13.4,7.9Hz,3H),1.06–0.95(m,4H),0.89–0.80(m,10H),0.74(s,3H),-0.01(d,J＝2.4Hz,6H);
13C NMR(125MHz,CDCl3)δ211.3,87.4,81.5,69.4,47.43,43.7,39.9,39.5,36.5,34.5,30.5,29.3,25.8,25.4,24.0,20.3,18.1,11.2,10.7,10.7,-4.5,-4.8;
HRMS (ESI) calculated molecular weight C 24H41O2Si[M+H]+: 389.2876; the molecular weight was found to be 389.2872.
Compound 25 (1.0 g,2.57mmol,1.0 equiv.) is dissolved in dichloromethane (20 mL) and trimethylsilyl triflate (0.698 mL,3.86mmol,1.5 equiv.) and diisopropylethylamine (2.23 mL,12.8mmol,5.0 equiv.) are added at 0deg.C and after completion, stirred at 25deg.C for half an hour. Subsequently, sodium bicarbonate (216 mg,2.57mmol,1.0 equiv.) was added. The reaction was directly freed from the solvent by rotary evaporation to give a pale yellow solid. The solid was dissolved in 1, 2-dichloroethane (250 mL), heated to 55deg.C, and catalyst ruthenium tris (acetonitrile) cyclopentadiene hexafluorophosphate (223 mg,0.514mmol,0.2 equiv.) was added and stirred for 12 hours. The solvent was dried by spin-drying and the resulting organic phase was concentrated to crude. The crude product was purified by silica gel column chromatography (hexane:EtOAc 20:1→10:1) to give compound 27 (809 mg, 81% yield) as a colorless oil.
Rf＝0.75(hexane/ethyl acetate＝10/1)；
(c＝0.6in MeOH)；
IR(film)λmax 2953,2857,1717,1464,1260,1105,885cm-1；
1H NMR(400MHz,CDCl3)δ5.39–5.32(m,1H),4.05(m,1H),3.60(dd,J＝8.7,7.5Hz,1H),2.70–2.59(m,1H),2.53–2.42(m,2H),2.22–2.11(m,2H),1.97–1.85(m,1H),1.79–1.73(m,3H),1.72–1.64(m,2H),1.61(d,J＝4.7Hz,1H),1.50–1.41(m,2H),1.41–1.32(m,2H),1.31–1.21(m,1H),1.12–0.95(m,2H),0.87(s,9H),0.70(s,3H),0.01(d,J＝2.7Hz,6H);
13C NMR(100MHz,CDCl3)δ208.8,140.8,118.0,81.2,53.3,51.8,50.0,45.0,43.6,42.9,36.5,31.0,29.4,28.5,25.8,23.9,23.6,22.0,18.1,11.5,-4.5,-4.8;
HRMS (ESI) calculated molecular weight C 24H41O2Si[M+H]+: 389.2876; the molecular weight was found to be 389.2874.
Compound 27 (5.0 g,12.9 mmol,1.0 equiv) was dissolved in ethanol (50 mL), triphenylphosphine (5.09 g,19.4 mmol,1.5 equiv), manganese acetylacetonate (6.55 g,25.8 mmol,2.0 equiv) and phenylsilane (3.19 mL,25.8 mmol,2.0 equiv) were added at 25 ℃ and stirred under an oxygen atmosphere for two hours. Subsequently, a saturated sodium sulfite solution (50 mL) was added, extracted with ethyl acetate (100 mL ×3), and the combined organic phases were washed once with saturated brine (200 mL), dried over Na 2SO4, and filtered to give a crude product in which the organic phase was concentrated. The crude product was purified by column chromatography on silica gel (hexane:EtOAc 10:1→4:1) to give compound 1 (3.36: 3.36 g, 64% yield) as a colourless oil.
Rf＝0.3(hexane/ethyl acetate＝4/1)；
IR(film)λmax 2930,2857,1717,1260,1105,1020,837,776 cm-1；
(c＝0.8 in MeOH)；
1H NMR(400 MHz,CDCl3)δ3.62–3.53(m,1H),3.17(t,J＝8.2 Hz,1H),2.60–2.38(m,2H),2.16–2.03(m,1H),1.97–1.84(m,2H),1.79(m,1H),1.64(m,3H),1.50–1.29(m,4H),1.19–1.11(m,1H),1.07–1.02(m,1H),0.96(td,J＝12.4,4.7 Hz,1H),0.87(s,10H),0.72(s,3H),0.64(td,J＝11.6,4.4 Hz,1H),0.00(d,J＝1.6 Hz,9H);
13C NMR(100 MHz,CDCl3)δ211.8,81.2,80.8,62.9,56.8,50.4,44.6,43.3,39.3,36.4,35.6,31.1,28.2,25.8,23.9,23.2,22.0,19.7,18.1,11.5,-4.5,-4.9;
HRMS (ESI) calculated molecular weight C 24H43O3Si[M+H]+: 407.2981; the molecular weight was found to be 407.2985.
Synthesis of Compound 3
Compound 1 (5 g,12.3 mmol,1.0 equiv) was dissolved in tetrahydrofuran (100 mL), and lithium bis (trimethylsilyl) amide (1.0M in THF,30.8 mL,30.8 mmol,2.5 equiv) and triethylamine (34.2 mL,246 mmol,20.0 equiv) were added dropwise at-78 ℃ and after completion, stirred at this temperature for one hour. Then, at this temperature, trimethylchlorosilane (3.12 mL,24.6 mmol,2.0 equiv) was added and stirred for 1 hour. Phosphate buffer solution (ph=7.4, 20 ml) was added, extraction was performed with ethyl acetate (80 mL ×3), the combined organic phases were washed once with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, the obtained crude concentrated organic phase was dissolved in acetonitrile (50 mL), palladium acetate (2.7 g,12.3 mmol,1.0 equiv) was added at 25 ℃. Then, stirring was carried out for 4 hours. Subsequently, the mixture was filtered and dried, and the obtained organic phase was concentrated to give crude compound 2.
Compound 2 was dissolved in tetrahydrofuran (100 mL), aqueous sodium hydroxide (2 M,12.3 mL,2.0 equiv) and hydrogen peroxide (30% in H 2 O,123 mL) were added and stirred at 66 ℃ for two hours. Then quenched by addition of saturated sodium sulfite (20 mL). The reaction was extracted with ethyl acetate, dried over sodium sulfate, filtered and the resulting organic phase was dried by spinning to give a concentrated crude product. The crude product was purified by silica gel column chromatography (hexane:etoac 10:1→5:1) to give compound 3 (3.36: 3.36 g, 65% yield) as a colourless oil.
Rf＝0.3(hexane/ethyl acetate＝4/1)；
(c＝0.8 in MeOH)；
IR(film)λmax 2953,2857,1797,1459,1256,1107,835,775 cm-1；
1H NMR(500MHz,CDCl3)δ4.06–3.29(m,3H),3.20(dd,J＝10.0,7.6Hz,1H),2.54(m,1H),2.32(d,J＝5.6Hz,1H),2.12(m,1H),2.00–1.89(m,1H),1.84–1.75(m,3H),1.55(dd,J＝12.2,10.1Hz,3H),1.16–0.97(m,3H),0.92(dd,J＝12.8,4.4Hz,2H),0.87(s,10H),0.74(s,3H),0.59(td,J＝12.0,4.1Hz,1H),-0.00(d,J＝2.0Hz,6H);
13C NMR(125MHz,CDCl3)δ207.6,81.2,77.7,62.5,60.8,58.0,57.3,50.30,44.6,40.1,36.6,33.9,31.1,28.5,25.8,23.8,22.0,19.7,18.1,11.5,-4.5,-4.9;
HRMS (ESI) calculated molecular weight C 24H41O4Si[M+H]+: 421.2774; the molecular weight was found to be 421.2772.
Synthesis of Compound 4
To a solution of compound 3 (500 mg,1.19mmol,1.0 equiv.) in tetrahydrofuran/water (20 mL/1 mL) was added samarium diiodide solution (0.5 m,5.96mL,2.98mmol,2.5 equiv.) at-78 ℃. The reaction mixture was stirred for 20 min, quenched with saturated aqueous sodium bicarbonate (20 mL), extracted with ethyl acetate, the combined organic layers were dried over anhydrous sodium sulfate, concentrated by vacuum filtration, and the crude product was purified by silica gel column chromatography (hexane:EtOAc 10:1→4:1) to give compound 4 (422 mg, 84% yield) as a yellow oil.
Rf＝0.4(hexane/ethyl acetate＝2/1)；
(c＝0.2in MeOH)；
IR(film)λmax 2930,2856,1684,1362,1111,880,773cm-1；
1H NMR(500MHz,CDCl3)δ4.34–3.74(m,1H),3.57(dd,J＝8.9,7.5Hz,1H),3.22(dd,J＝9.3,7.7Hz,1H),3.03–2.65(m,2H),2.45–2.11(m,1H),1.92(m,5H),1.79(d,J＝12.6Hz,2H),1.68(d,J＝3.6Hz,2H),1.63–1.54(m,2H),1.48–1.38(m,3H),1.21–1.13(m,1H),1.06–0.94(m,3H),0.87(s,9H),0.72(s,3H),0.72–0.56(m,1H),0.00(d,J＝2.3Hz,6H);
13C NMR(125MHz,CDCl3)δ208.5,81.2,80.8,69.0,64.0,57.4,52.6,50.4,44.7,39.3,36.4,33.2,31.2,31.1,28.9,25.9,23.9,19.6,18.1,11.5,-4.5,-4.8;
HRMS (ESI) calculated molecular weight C 24H41O3Si[M+H-H2O]+: 405.2825; the molecular weight was found to be 405.2827.
Synthesis of Compound 5
To a solution of compound 4 (2.0 g,4.72mmol,1.0 equiv.) in dichloromethane (20.0 mL) were added 4-dimethylaminopyridine (115 mg,0.994mmol,0.2 equiv.), N-diisopropylethylamine (8.24 mL,47.2mmol,10.0 equiv.) and chloromethyl methyl ether (0.716 mL,9.44mmol,2.0 equiv.). After completion of the reaction, quenched with saturated aqueous sodium bicarbonate (20 mL), extracted with ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated by vacuum filtration. Purification by column chromatography on silica gel (hexane:EtOAc 10:1→4:1) afforded compound 5 (1.92 g, 87% yield) as a yellow oil.
Rf＝0.7(hexane/ethyl acetate＝4/1)；
(c＝0.3in MeOH)；
IR(film)λmax 2953,2927,2855,1683,1033,1036,1775cm-1；
1HNMR(500MHz,CDCl3)δ 4.70(q,J＝6.9Hz,2H),3.79(dt,J＝8.2,4.2Hz,1H),3.57(dd,J＝8.8,7.5Hz,1H),3.37(s,3H),3.23(t,J＝8.5Hz,1H),2.86(dd,J＝12.7,8.6Hz,1H),2.77–2.70(m,1H),2.21–2.10(m,1H),1.95(d,J＝12.6Hz,3H),1.80–1.66(m,3H),1.58(d,J＝9.2Hz,2H),1.45–1.39(m,3H),1.37–1.28(m,1H),1.22–1.11(m,1H),1.08–1.00(m,1H),0.96–0.90(m,1H),0.87(s,9H),0.73(s,3H),0.70–0.62(m,1H),-0.00(d,J＝2.4Hz,6H);
13C NMR(125MHz,CDCl3)δ208.5,95.1,81.2,80.5,73.9,64.3,57.3,55.6,50.4,49.6,44.7,39.4,36.5,33.2,31.1,29.0,28.8,25.9,23.9,19.6,18.1,11.5,-4.5,-4.8;
HRMS (ESI) calculated molecular weight C 24H45O4Si[M+H-H2O]+: 449.3087; the molecular weight was found to be 449.3088.
Synthesis of Compound 6
1, 8-Diazabicyclo [5.4.0] undec-7-ene (4.80 mL,32.2mmol,15.0 equiv.) is added to a solution of compound 5 (1.0 g,2.14mmol,1.0 equiv.) in tetrahydrofuran (50 mL). After stirring the reaction mixture at 66 ℃ for 10 hours, it was quenched with saturated aqueous ammonium chloride (20 mL), extracted with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, concentrated by vacuum filtration, and the crude product was purified by column chromatography on silica gel (hexane:etoac 10:1→4:1) to give compound 6 (583 mg, 73% yield) as a yellow oil.
Rf＝0.45(hexane/ethyl acetate＝4/1)；
(c＝0.2in MeOH)；
IR(film)λmax 3445,2953,2930,2857,1688,1466,1252,1144,1043,835cm-1；
1H NMR(500MHz,CD2Cl2)δ4.86–4.46(m,2H),4.23(m,1H),3.58(t,J＝8.3Hz,1H),3.32(s,3H),2.99(t,J＝8.9Hz,1H),2.44–2.27(m,1H),2.20–1.84(m,8H),1.46–1.37(m,7H),1.12–0.95(m,3H),0.88(s,9H),0.75(s,3H),0.02(d,J＝3.3Hz,6H);
13C NMR(125MHz,CD2Cl2)δ212.2,96.4,82.2,78.7,76.6,62.0,58.8,55.0,50.4,50.5,43.8,41.7,40.3,36.4,33.1,31.1,27.5,26.1,24.4,24.2,18.5,11.6,-4.3,-4.6;
HRMS (ESI) calculated molecular weight C 26H46NaO5Si[M+Na]+: 489.3012; the molecular weight was found to be 489.3010.
Synthesis of Compound 9
To a solution of compound 6 (1.0 g,2.14mmol,1.0 equiv.) in tetrahydrofuran (20 mL) was added diisobutylaluminum hydride (1.5M toluene solution, 2.85mL,4.28mmol,2.0 equiv.) at-78 ℃. The resulting mixture was stirred for 1 hour, then copper tartrate (1.14 g,5.35mmol,2.5 equiv.) was added. After stirring for 30 minutes tetrabutylammonium fluoride (1M in THF,8.56mL,8.56mmol,4.0equiv.) was added, heated to 66 ℃ and stirred for 10 hours. Quench with saturated ammonium chloride (50 mL) and extract with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, concentrated by vacuum filtration, and the crude product was purified by silica gel column chromatography to give compound 7 (493 mg, 65% yield).
The resulting compound 7 (493 mg,1.39mmol,1.0 equiv.) was dissolved in methylene chloride (20 mL), and dess-martin oxidant (707 mg,1.67mmol,1.2 equiv.) and sodium bicarbonate (401 mg,5.01mmol,3.0 equiv.) were added at 0 ℃ followed by heating to 25 ℃ and stirring for 1 hour. Quench with saturated sodium sulfite (10 mL) and extract with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, concentrated by vacuum filtration, and the crude product purified by flash column chromatography on silica gel (hexane:etoac 10:1→4:1) to give compound 8 (381.2 mg, 78% yield) as a yellow oil.
Lithium bistrimethylsilylamino (1.0M in THF,5.40mL,5.4mmol,5.0equiv) and triethylamine (2.99 mL,21.6mmol,20.0 equiv.) are added to a solution of compound 8 (383mg, 1.08 mmol) in tetrahydrofuran (10 mL) at-78 ℃ and the resulting mixture is stirred for 40 min. Trimethylchlorosilane (0.684 ml,5.4mmol,5.0 equiv.) is added and stirred for 1 hour at-78 ℃, and then heated to 25 ℃ and stirred for 2 hours. Then quenched with phosphate buffer (ph=7.4, 20 ml), extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate and concentrated by vacuum filtration. The crude product was dissolved in acetonitrile (10 mL) and palladium acetate (180.0 mg,1.08mmol,1.0 equiv.) was added. After stirring the reaction mixture for 4 hours, it was concentrated by vacuum filtration, and the crude product was purified by silica gel column chromatography (hexane:EtOAc 10:1→4:1) to give compound 9 (437 mg, 82% yield) as a colourless oil.
Rf＝0.6(hexane/ethyl acetate＝10/1)；
(c＝0.67in MeOH)；
IR(film)λmax 2949,2926,2357,1717,1250,1067cm-1；
1H NMR(500MHz,CDCl3)δ7.62(dd,J＝6.0,1.3Hz,1H),6.04(dd,J＝6.0,3.1Hz,1H),4.68–4.55(m,2H),4.17(m,1H),3.53(d,J＝0.8Hz,1H),3.35(d,J＝3.5Hz,3H),2.35–2.25(m,2H),2.13–1.90(m,5H),1.93–1.83(m,2H),1.76(m,2H),1.50(m,4H),1.25(td,J＝9.7,5.1Hz,1H),1.07(s,3H),0.17(s,9H),0.11(s,9H);
13C NMR(125MHz,CDCl3)δ212.2,158.0,130.4,94.9,82.9,78.2,75.7,55.3,55.1,54.0,51.9,50.0,47.7,36.2,35.7,33.3,28.0,27.4,25.3,19.6,1.3,-0.0;
HRMS (ESI) calculated molecular weight C 26H47O5Si2[M+H]+: 495.2957; the molecular weight was found to be 495.2954.
Synthesis of Compound 10
To a solution of compound 9 (642.0 mg,1.30mmol,1.0 equiv.) in benzotrifluoride (40 mL) were added N, N-diisopropylethylamine (12.4 mL,71.5mmol,55.0 equiv.) and silica gel (6.0 g,98.7mmol,76.0 equiv.). The reaction was stirred for 18 hours. The mixture was concentrated by filtration in vacuo and the crude product was purified by column chromatography on silica gel (hexane:EtOAc 10:1→4:1) to give compound 10 (482 mg, 75% yield) as a yellow oil.
Rf＝0.6(hexane/ethyl acetate＝10/1)；
(c＝0.67in MeOH)；
IR(film)λmax 2953,2341,1250,1057,752cm-1；
1H NMR(500MHz,CDCl3)δ5.56(d,J＝2.1Hz,1H),4.65(q,J＝6.6Hz,2H),4.17(ddd,J＝7.2,3.6,1.6Hz,1H),3.53(d,J＝1.5Hz,1H),3.35(s,3H),3.03–2.74(m,2H),2.40–2.19(m,2H),2.15–2.07(m,2H),2.00(t,J＝9.1Hz,1H),1.97–1.91(m,1H),1.74–1.65(m,4H),1.51–1.43(m,3H),1.28(d,J＝9.2Hz,1H),1.15–1.07(m,3H),0.19(s,9H),0.12(s,9H);
13C NMR(125MHz,CDCl3)δ222.8,154.0,113.7,96.1,84.4,80.2,77.1,55.6,55.2,52.3,50.8,48.7,41.6,37.5,37.1,37.0,33.1,28.8,25.1,19.7,2.5,1.2;
HRMS (ESI) calculated molecular weight C 26H47O5Si2[M+H]+: 495.2962; the molecular weight was found to be 495.2957.
Synthesis of Compound 11
Triphenylphosphine (393 mg,1.5mmol,1.5 equiv.), manganese diacetylacetonate (1.01 g,4.0mmol,4.0 equiv.) and phenylsilane (0.370 mL,3.0mmol,3.0 equiv.) were added sequentially to a solution of compound 10 (495mg, 1.0mmol,1.0 equiv.) in ethanol (10 mL) at 25℃under an oxygen atmosphere. Stirring was continued for 2 hours. The reaction was detected by thin layer chromatography. The reaction mixture was then concentrated in vacuo to give the crude product.
To a solution of the crude product in tetrahydrofuran (10 mL) at 60℃was added, in order, trimethylsilaimidazole (1.4 g,10.0 eq.) and tetrabutylammonium fluoride (1.0M, 0.1mL,0.1mmol,0.1 eq.). After stirring for 1 hour, quench with saturated aqueous sodium bicarbonate (20 mL), extract with ethyl acetate, dry the combined organic phases over anhydrous sodium sulfate, concentrate by vacuum filtration, and purify the crude by silica gel column chromatography (hexane: etOAc 50:1→10:1) to give compound 11 as a yellow oil (410 mg, 70% yield).
Rf＝0.65(hexane/ethyl acetate＝10/1)；
(c＝0.80in MeOH)；
IR(film)λmax 2953,2342,1741,1249,1062,1045,837,752cm-1；
1H NMR(500MHz,CDCl3)δ4.64(d,J＝7.0Hz,2H),4.23–4.13(m,1H),3.54(s,1H),3.32(d,J＝4.1Hz,3H),2.44(dd,J＝18.3,9.6Hz,1H),2.39–2.30(m,1H),2.22–1.98(m,9H),1.98–1.87(m,1H),1.85–1.77(m,1H),1.70–1.55(m,2H),1.50(m,2H),1.41–1.27(m,2H),0.96(s,3H),0.15(s,9H),0.15(s,9H),0.12(s,9H);
13C NMR(125MHz,CDCl3)δ219.3,96.0,87.8,84.6,80.4,77.1,55.6,55.2,54.4,48.2,46.0,41.0,37.1,37.0,33.4,29.1,27.7,25.5,22.6,18.2,2.6,2.5;
HRMS (ESI) calculated molecular weight C 29H57O6Si3[M+H]+ Exact Mass 585.3457; the molecular weight was found to be 585.3453.
Synthesis of Compound 12
A solution of lithium bis (trimethylsilyl) amide (1.5M, 1.00mL,1.5mmol,1.5 equiv.) is added to a solution of compound 11 (585 mg,1.0mmol,1.0 equiv.) in tetrahydrofuran (10 mL) at-78deg.C. Stirred for 1 hour, comins reagents (589.1 mg,1.5mmol,1.5 equiv.) were added. After stirring at-78 ℃ for 1 hour, the reaction was removed from the cold bath and stirring was continued at 25 ℃. After confirming completion of the reaction by thin layer chromatography, it was quenched with saturated aqueous sodium bicarbonate (20 mL), extracted with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, concentrated by vacuum filtration, and the crude product was purified by silica gel column chromatography (hexane:EtOAc 50:1→1:1) to give compound 12 (617.0 mg, 86% yield) as a yellow oil.
Rf＝0.8(hexane/ethyl acetate＝10/1)；
(c＝0.11in MeOH)；
IR(film)λmax 2953,2365,2345,1211,1144,1045,837,752cm-1；
1H NMR(500MHz,CDCl3)δ5.44(d,J＝1.7Hz,1H),4.65(q,J＝6.6Hz,2H),4.17(dddd,J＝11.1,9.3,7.3,5.7Hz,1H),3.60(s,1H),3.35(s,3H),2.47(dd,J＝16.3,1.6Hz,1H),2.34(d,J＝12.4Hz,1H),2.25(dd,J＝16.3,3.4Hz,1H),2.10–1.99(m,3H),1.99–1.85(m,3H),1.82–1.76(m,1H),1.63(d,J＝11.4Hz,1H),1.56(s,3H),1.46(dd,J＝16.0,7.3Hz,3H),1.33–1.23(m,4H),1.02(s,3H),0.17(s,9H),0.11(s,9H),0.09(s,9H);
13C NMR(125MHz,CDCl3)δ154.1,106.1,93.7,85.1,82.1,78.0,52.8,52.7,47.7,46.3,45.9,41.9,35.0,34.5,34.3,33.2,25.2,20.4,11.9,0.1,0.00,-1.3;
HRMS (ESI) calculated molecular weight C 30H56O8SSi3[M+H]+: 717.2856; the molecular weight was found to be 717.2850.
Synthesis of Compound 13
To a solution of compound 12 (716.0 mg,1.0mmol,1.0 equiv.) in N, N-dimethylformamide/water (10 mL/1 mL) was added compound A (266.5 mg,1.2mmol,1.2 equiv.), 1-bis (diphenylphosphino) ferrocene palladium dichloride (72.6 mg,0.1mmol,0.1 equiv.) and potassium phosphate trihydrate (665 mg,2.5mmol,2.5 equiv.). The reaction mixture was heated to 60 ℃, stirred for 2 hours, quenched with saturated aqueous sodium bicarbonate (20 mL), extracted with ethyl acetate, the combined organic phases dried over anhydrous sodium sulfate, concentrated by vacuum filtration, and the crude purified silica gel (hexane: etOAc 20:1→5:1) by column chromatography to give compound 13 (563.0 mg, 85% yield) as a yellow oil.
Rf＝0.55(hexane/ethyl acetate＝4/1)；
(c＝0.67in MeOH)；
IR(film)λmax 3638,2951,2359,1748,1250,1047,837cm-1；
1H NMR(500MHz,CDCl3)δ7.45(s,1H),7.42(dd,J＝9.7,2.6Hz,2H),6.33(dd,J＝9.6,0.8Hz,1H),5.71(s,1H),4.65(q,J＝6.7Hz,2H),4.30–4.08(m,1H),3.60(s,1H),3.36(s,3H),2.51(d,J＝16.4Hz,1H),2.39–2.33(m,1H),2.29(dd,J＝17.5,3.2Hz,1H),2.14–2.01(m,1H),1.95(dt,J＝13.6,4.6Hz,1H),1.89–1.77(m,2H),1.67(s,1H),1.54–1.44(m,3H),1.36–1.19(m,4H),1.08(s,3H),0.18(s,9H),0.12(s,9H),0.03(s,9H);
13C NMR(125MHz,CDCl3)δ161.3,147.4,145.3,144.3,124.8,116.4,116.1,96.1,90.7,84.8,80.5,77.2,55.3,55.2,52.6,48.6,48.4,44.3,38.7,38.6,37.6,37.0,28.0,23.5,17.0,2.8,2.5,1.2;
HRMS (ESI) calculated molecular weight C 34H59O7Si3[M+H]+: 663.3569; the molecular weight was found to be 663.3563.
Synthesis of Compound 14
M-chloroperoxybenzoic acid (276.1 mg,75%,1.20mmol,1.2 equiv.) is added to a solution of compound 13 (662.0 mg,1.0mmol,1.0 equiv.) in dichloromethane (20 mL) at 25 ℃. After stirring at the same temperature for 4 hours, borane dimethyl sulfide (2.5 m in thf,600 μl,1.50mmol,1.5 equiv.) was added to the reaction mixture at0 ℃. After stirring the resulting reaction mixture for 1.5h, it was quenched with saturated aqueous sodium bicarbonate (20 mL) and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, concentrated by vacuum filtration and the crude product purified by column chromatography on silica gel (hexane:EtOAc 10:1 →
3:1) To give compound 14 (428.7 mg, 63% yield) as a yellow oil.
Rf＝0.25(hexane/ethyl acetate＝4/1)；
(c＝0.8in MeOH)；
IR(film)λmax 2951,2364,1726,1719,1249,1066,979,839cm-1；
1H NMR(500MHz,CDCl3)δ7.52(d,J＝10.1Hz,1H),5.88(d,J＝10.1Hz,1H),5.18(q,J＝14.3Hz,2H),4.69–4.62(m,2H),4.55(dd,J＝11.8,6.5Hz,1H),4.16(m,1H),3.54(s,1H),3.35(d,J＝3.1Hz,3H),2.91(d,J＝11.9Hz,1H),2.38–2.30(m,1H),2.11(dd,J＝14.4,6.6Hz,2H),2.01(t,J＝9.0Hz,1H),1.98–1.94(m,2H),1.85(m,12.4Hz,1H),1.67–1.58(m,2H),1.52–1.41(m,7H),1.35–1.22(m,4H),0.18(d,J＝1.2Hz,18H),0.12(s,9H);
13C NMR(125MHz,CDCl3)δ164.0,1560.5,1340.2,123.9,117.8,96.1,94.7,84.3,80.2,77.1,72.0,68.9,55.5,55.2,51.5,48.6,48.4,40.7,40.7,38.9,37.4,36.9,28.3,24.2,22.9,3.0,2.4,1.1;
HRMS (ESI) calculated molecular weight C 34H61O8Si3[M+H]+: 681.3669; the molecular weight was found to be 681.3669.
Synthesis of Compound 15
To a solution of compound 14 (681.4 mg,1.0mmol,1.0 equiv.) in dichloromethane (20 mL) at 25deg.C was added dess-Martin oxidant (509.0 mg,1.2mmol,1.2 equiv.) and sodium bicarbonate (240 mg,3.0mmol,2.5 equiv.). After stirring at the same temperature for 2 hours, quench with saturated aqueous sodium bisulphite (20 mL), extract with ethyl acetate, dry the combined organic phases over anhydrous sodium sulfate, concentrate by vacuum filtration, and purify the crude by column chromatography on silica gel (hexane: etOAc 10:1→3:1) to give compound 15 as a yellow oil (576.6 mg, 85% yield).
Rf＝0.45(hexane/ethyl acetate＝4/1)；
(c＝0.31in MeOH)；
IR(film)λmax 3638,2941,2864,1728,1238,1134,1040,758cm-1；
1H NMR(500MHz,CDCl3)δ7.47(d,J＝10.2Hz,1H),6.17(d,J＝10.1Hz,1H),5.67(dd,J＝39.0,17.7Hz,2H),4.65(q,J＝6.7Hz,2H),4.17(m,1H),3.58(s,1H),3.35(d,J＝2.5Hz,3H),2.59(d,J＝18.0Hz,1H),2.39–2.35(m,2H),2.13–2.04(m,2H),2.04–1.94(m,3H),1.92–1.80(m,3H),1.69–1.58(m,2H),1.55–1.44(m,3H),1.40–1.31(m,2H),1.27(d,J＝14.2Hz,2H),0.19(s,9H),0.11(s,9H),0.05(s,9H);
13C NMR(125MHz,CDCl3)δ206.7,162.2,147.2,138.7,133.0,123.0,96.1,86.0,84.4,80.3,77.1,69.6,55.4,55.2,50.8,48.4,48.1,46.0,41.7,38.2,37.4,36.9,28.2,23.7,22.6,2.5,2.4,1.1;
HRMS (ESI) calculated molecular weight C 34H59O8Si3[M+H]+: 679.3512; the molecular weight was found to be 679.3508.
Synthesis of Compound 16
To a solution of compound 15 (339.2 mg,0.5mmol,1.0 equiv.) in tetrahydrofuran (20 mL) was added 1, 8-diazabicyclo [5.4.0] undec-7-ene (0.149 mL,1.00mmol,2.0 equiv.) at 25 ℃. Stirred for 30 minutes at 25 ℃, then cooled to-98 ℃, and lithium bistrimethylsilylamino (1.0M in THF,2.50mL,2.50mmol,5.0equiv.) was added. Stirred for 2 hours, quenched with saturated aqueous sodium bicarbonate (20 mL) and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, concentrated by vacuum filtration, and the crude product was purified by column chromatography on silica gel (hexane:EtOAc 10:1→3:1) to give compound 16 (223.6 mg, 76% yield) as a yellow oil.
Rf＝0.3(hexane/ethyl acetate＝4/1)；
(c＝0.33in MeOH)；
IR(film)λmax 2951,2882,2355,2320,1747,1697,1508,1045,839cm-1；
1H NMR(500MHz,CDCl3)δ7.31(d,J＝1.8Hz,1H),7.04(dd,J＝9.6,2.5Hz,1H),6.31(d,J＝9.4Hz,1H),6.01(s,1H),4.65(q,J＝6.7Hz,2H),4.21–4.13(m,1H),3.63(s,1H),3.36(s,3H),3.09(s,1H),2.61(t,J＝9.6Hz,1H),2.31(m,2H),2.17–2.09(m,2H),2.04(t,J＝9.7Hz,1H),1.94(s,1H),1.81(d,J＝5.7Hz,2H),1.78(d,J＝6.1Hz,2H),1.55–1.40(m,4H),0.96(s,3H),0.20(s,9H),0.13(s,9H);
13C NMR(125MHz,CDCl3)δ205.0,191.9,161.3,150.9,145.2,125.0,116.2,114.9,96.1,83.9,79.9,76.9,60.9,55.5,55.2,52.0,48.6,47.6,40.1,39.1,37.0,36.8,28.6,26.0,22.4,2.4,1.2;
HRMS (ESI) calculated molecular weight C 31H49O7Si2[M+H]+: 589.3017; the molecular weight was found to be 589.3009.
Synthesis of Compound 17
To a tetrahydrofuran solution (2 mL) of compound 16 (58.8 mg,0.100mmol,1.0 equiv.) were added (R) -2-methyl-CBS-oxazoleboronine (1M toluene solution, 0.20mL,0.200mmol,2.0 equiv.) and borane dimethyl sulfide solution (2.5M in THF,80mL,0.200mmol,2.0equiv.) at 25 ℃. The resulting mixture was stirred for 1 hour, after completion of which the reaction was monitored by TLC and 4-dimethylaminopyridine (3.7 mg,0.003mmol,0.3 equiv.), triethylamine (101.2 mg,1.0mmol,10.0 equiv.) and acetic anhydride (51.1 mg,0.500mmol,5.0 equiv.) were added. After stirring for 1 hour at 25℃was quenched with methanol (0.5 mL), concentrated in vacuo and the crude product was purified by column chromatography on silica gel (hexane:EtOAc 50:1→10:1) to give compound 17 as a yellow oil (55.6 mg, 88% yield).
Rf＝0.7(hexane/ethyl acetate＝4/1)；
(c＝0.2in MeOH)；
IR(film)λmax 2951,2926,2358,2322,1747,1732,1109,1045,986,752cm-1；
1H NMR(500MHz,CDCl3)δ7.54–7.50(m,1H),7.39(d,J＝1.6Hz,1H),6.27(dd,J＝9.7,0.9Hz,1H),5.61(d,J＝2.3Hz,1H),5.56(dd,J＝6.4,2.6Hz,1H),4.65(q,J＝6.7Hz,2H),4.26–4.11(m,1H),3.58(s,1H),3.35(s,3H),2.70(d,J＝6.4Hz,1H),2.31(m,2H),2.08(dd,J＝14.2,10.8Hz,2H),2.01(d,J＝3.7Hz,5H),1.90(dd,J＝14.3,8.3Hz,1H),1.80(dd,J＝9.7,3.6Hz,1H),1.77–1.62(m,3H),1.56(s,5H),1.51–1.43(m,3H),1.31–1.22(m,2H),1.04(s,4H),0.18(s,9H),0.12(s,9H);
13C NMR(125MHz,CDCl3)δ170.1,163.1,161.6,150.4,146.9,117.9,116.0,114.8,96.1,84.2,80.0,79.3,77.2,55.5,55.2,55.2,51.5,48.7,39.9,37.5,37.1,37.0,29.2,25.8,22.0,21.4,2.5,1.2;
HRMS (ESI) calculated molecular weight C 33H53O8Si2[M+H]+: 633.3279; the molecular weight was found to be 633.3269.
Synthesis of Compound bufogargarizin B (1)
To a solution of compound 17 (63.2 mg,0.1mmol,1.0 equiv.) in acetone (2 mL) and distilled water (200. Mu.L) was added NBS (21.4 mg,0.12mmol,1.2 equiv.) under argon at 25 ℃. After stirring for 1 hour, sodium hydroxide solution (2.0M aq.,200 μl,0.4mmol,4 equiv.) was added and stirred for 5 minutes, followed by tetrabutylammonium fluoride (1M in THF,0.40mL,0.40mmol,4.0equiv.). After stirring at 25 ℃ for 2 hours, it was quenched with saturated aqueous sodium bicarbonate (10 mL), extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate and concentrated by vacuum filtration. The crude product was used directly in the next step without further purification.
To a solution of the crude product in methylene chloride (4 ml) was added pyridine dichromate (PDC; 56.4mg,0.15mmol,1.5 eq.). The resulting mixture was stirred for 2 hours, and acetic anhydride (15.3 mg,0.15mmol,1.5 equiv.) was added. After 1 hour, the mixture was quenched with saturated aqueous sodium sulfite (10 mL) and extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was used directly in the next step without further purification.
To a solution of the above crude product in acetonitrile (2 mL) was added distilled water (200. Mu.L) and lithium tetrafluoroborate (46.9 mg,0.5mmol,5.0 equiv.). Stirred at 82℃for 1.5 hours. Then quenched with saturated aqueous sodium bicarbonate (10 mL), extracted with ethyl acetate and the combined organic phases were dried over anhydrous sodium sulfate and concentrated by vacuum filtration. The crude product was purified by column chromatography on silica gel (hexane:EtOAc 2:1→4:3) to give bufogargarizin B (1) as a white powder (14.6 mg, 32% overall yield).
Rf＝0.2(ethyl acetate,100％)；
(c＝0.2in MeOH)；
Isolated:(c＝0.1,in MeOH),reported by Ye,et al.4
IR(film)λmax 3638,2926,2858,1264,1084,1021,801cm-1；
1H NMR(500MHz,CD3OD)δ8.00(d,J＝8.3Hz,1H),7.37(s,1H),6.24(d,J＝9.7Hz,1H),5.50(dd,J＝9.3,1.1Hz,1H),4.41–4.34(m,1H),3.76(s,1H),3.11(dd,J＝8.3,8.3Hz,1H),2.95(d,J＝9.3Hz,1H),2.74(ddd,J＝11.9,11.9,3.6Hz,1H),2.03(dt,J＝9.4,7.8Hz,2H),2.01–1.92(m,3H),1.86(s,2H),1.84–1.73(m,2H),1.67(m,1H),1.63–1.52(m,2H),1.53–1.46(m,2H),1.41(dd,J＝12.7,10.2Hz,1H),1.19(dd,J＝15.0,11.2Hz,1H),0.86(s,3H);
13C NMR(125MHz,CD3OD)δ212.7,171.6,164.0,153.7,150.8,118.2,114.2,79.9,76.4,72.3,71.8,62.7,61.1,58.1,51.9,51.3,46.5,40.0,39.7,39.5,35.7,24.3,22.5,20.4,17.5;
HRMS (ESI) calculated molecular weight C 25H31O8[M+H]+: 459.2013; the molecular weight was found to be 459.2017.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples merely represent a few embodiments of the present invention, which facilitate a specific and detailed understanding of the technical solutions of the present invention, but are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. It should be understood that, based on the technical solutions provided by the present invention, those skilled in the art may obtain technical solutions through logical analysis, reasoning or limited experiments, which are all within the scope of protection of the appended claims. The scope of the patent of the invention should therefore be determined with reference to the appended claims, which are to be construed as in accordance with the doctrines of claim interpretation.

Claims (10)

1. A method of preparing bufogargarizin B comprising the steps of:
Compound 1 Mixing lithium bis (trimethylsilyl) amide, triethylamine and a first organic solvent, carrying out enolization reaction, carrying out silylation reaction on the enolization reaction product and trimethylchlorosilane, and carrying out oxidation reaction on the silylation reaction product and palladium acetate in a second organic solvent to prepare a compound 2Oxidizing the compound 2, sodium hydroxide aqueous solution and hydrogen peroxide in a third organic solvent to prepare a compound 3
The compound 3 and samarium diiodide are subjected to ring opening reaction in a fourth organic solvent to prepare a compound 4
Mixing the compound 4, chloromethyl methyl ether, 4-dimethylaminopyridine, N-diisopropylethylamine and a fifth organic solvent for hydroxyl protection reaction to prepare a compound 5
The compound 5 and 1, 8-diazo hetero double spiro [5.4.0] undec-7-alkene are subjected to series reaction of inverse aldol condensation and trans-cyclic aldol condensation in a sixth organic solvent to prepare a compound 6
The compound 6 and diisobutyl aluminum hydride are subjected to reduction reaction in a seventh organic solvent, and the product of the reduction reaction and tetrabutylammonium fluoride are subjected to desilication reaction to prepare a compound 7Oxidizing the compound 7, dess-martin oxidant, sodium bicarbonate and eighth organic solvent to prepare compound 8Mixing the compound 8, lithium bistrimethylsilylamino, triethylamine and a ninth organic solvent, carrying out enolization reaction, carrying out silicon-based reaction on the enolization reaction product and trimethylchlorosilane, carrying out oxidation reaction on the silicon-based reaction product and palladium acetate in the tenth organic solvent, and preparing the compound 9
The compound 9, N-diisopropylethylamine and silica gel are mixed with an eleventh organic solvent to carry out double bond shift reaction to prepare a compound 10
Mixing the compound 10, triphenylphosphine, manganese diacetylacetonate, phenylsilane and a twelfth organic solvent in an oxygen atmosphere, carrying out hydration reaction, mixing a hydration reaction product, trimethylsilicon imidazole and tetrabutylammonium fluoride, and carrying out a silicon-based reaction to prepare a compound 11
The compound 11, the lithium bistrimethylsilylamino and Comins reagent are mixed with thirteenth organic solvent to carry out triflate esterification reaction to prepare compound 12
The compound 12,Mixing with catalyst, and performing Suzuki coupling reaction in fourteenth organic solvent to obtain compound 13
The compound 13 and m-chloroperoxybenzoic acid are subjected to epoxidation reaction in a fifteenth organic solvent, and the product of the epoxidation reaction and borane dimethyl sulfide are subjected to reduction, double bond migration and ring-opening oxygen tandem reaction to prepare a compound 14
The compound 14, the dess-martin oxidant, the sodium bicarbonate and the sixteenth organic solvent are mixed for oxidation reaction to prepare a compound 15
Subjecting the compound 15 and 1, 8-diazabicyclo [5.4.0] undec-7-ene to elimination reaction in seventeenth organic solvent, and subjecting the product of elimination reaction and lithium bis (trimethylsilyl) amide to isomerization reaction to prepare a compound 16
The compound 16, (R) -2-methyl-CBS-oxazoloborane, borane dimethyl sulfide and eighteenth organic solvent are mixed for reduction reaction, and the product of the reduction reaction, 4-dimethylaminopyridine, triethylamine and acetic anhydride are mixed for acetylation reaction, thus preparing the compound 17
Under argon atmosphere, the compound 17, sodium hydroxide and N-bromosuccinimide are subjected to epoxidation reaction in a nineteenth organic solvent, a product of the epoxidation reaction is subjected to desilication reaction with tetrabutylammonium fluoride, the product of the desilication reaction, pyridine dichromate and acetic anhydride are mixed, oxidation reaction is carried out, the product of the oxidation reaction and lithium tetrafluoroborate are subjected to deprotection reaction in a twentieth organic solvent, and bufogargarizin B is prepared, wherein the structural formula of bufogargarizin B is shown as follows:
2. The method of preparing bufogargarizin B according to claim 1, wherein one or more of the following conditions are met during the preparation of the compound 4 from the compound 3:
(1) The molar ratio of the compound 3 to the samarium diiodide is 1 (2.3-2.7);
(2) The ring-opening reaction temperature is-78 ℃ + -5 ℃.
3. The method of preparing bufogargarizin B according to claim 1, wherein one or more of the following conditions are met during the preparation of the compound 6 from the compound 5:
(1) The mol ratio of the compound 5 to the 1, 8-diazabicyclo [5.4.0] undec-7-ene is 1 (14-16);
(2) The temperature of the tandem reaction of the inverse aldol condensation and the trans-cyclic aldol condensation is 66 ℃ +/-5 ℃.
4. The method of preparing bufogargarizin B according to claim 1, wherein one or more of the following conditions are met during the preparation of the compound 9 from the compound 8:
(1) The molar ratio of the compound 8 to the lithium bis (trimethylsilyl) amide to the triethylamine to the trimethylchlorosilane to the palladium acetate is 1 (4.5-5.5), 18-22 (4.5-5.5) and 0.8-1.2;
(2) The enolization reaction temperature is-78+/-5 ℃;
(3) The temperature of the silicon-based reaction is-78+/-5 ℃;
(4) The temperature of the oxidation reaction was 25 ℃ + -5 ℃.
5. The method of preparing bufogargarizin B according to claim 1, wherein one or more of the following conditions are met during the preparation of the compound 10 from the compound 9:
(1) The mol ratio of the compound 9 to the N, N-diisopropylethylamine to the silica gel is 1 (50-60) (70-80);
(2) The temperature of the double bond shift reaction is 15-30 ℃.
6. The method of preparing bufogargarizin B according to claim 1, wherein one or more of the following conditions are met during the preparation of the compound 13 from the compound 12:
(1) The compound 12 and the The molar ratio of (1) to (1.4);
(2) The temperature of the suzuki coupling reaction is 60+/-5 ℃.
7. The method of preparing bufogargarizin B according to claim 1, wherein one or more of the following conditions are met during the preparation of the compound 14 from the compound 13:
(1) The molar ratio of the compound 13, the m-chloroperoxybenzoic acid and the borane dimethyl sulfide is 1 (1-1.4) (1.3-1.7);
(2) The temperature of the epoxidation reaction is 25+/-5 ℃;
(3) The temperature of the serial reaction of reduction, double bond migration and ring opening oxygen is 0+/-5 ℃.
8. The method of preparing bufogargarizin B according to claim 1, wherein one or more of the following conditions are met during the preparation of the compound 15 from the compound 14:
(1) The molar ratio of the compound 14, the dess-martin oxidant and the sodium bicarbonate is 1 (1-1.4): 2.3-2.7);
(2) The temperature of the oxidation reaction was 25 ℃ + -5 ℃.
9. The method of preparing bufogargarizin B according to claim 1, wherein one or more of the following conditions are met during the preparation of the compound 16 from the compound 15:
(1) The molar ratio of the compound 15, the 1, 8-diazabicyclo [5.4.0] undec-7-ene and the lithium bistrimethylsilyl amide is 1 (1.8-2.2): 4.5-5.5);
(2) The temperature of the elimination reaction is 25+/-5 ℃;
(3) The temperature of the isomerization reaction was-98 ℃ + -5 ℃.
10. The method of preparing bufogargarizin B according to claim 1, wherein one or more of the following conditions are met during the preparation of bufogargarizin B from the compound 17:
(1) The molar ratio of the compound 17, the sodium hydroxide, the N-bromosuccinimide, the tetrabutylammonium fluoride, the pyridine dichromate, the acetic anhydride and the lithium tetrafluoroborate is 1 (3.8-4.2), 1-1.4, 3.8-4.2, 1.3-1.7 and 4.5-5.5;
(2) The temperature of the epoxidation reaction is 25+/-5 ℃;
(3) The desilication reaction temperature is 25+/-5 ℃;
(4) The temperature of the oxidation reaction is 15-30 ℃;
(5) The temperature of the deprotection reaction was 82 ℃ + -5 ℃.
CN202310040068.1A 2023-01-12 Bufogargarizin B preparation method Pending CN118324845A (en)

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