CN114560760B - Synthesis method of euphorbiaceae diterpene Pepluanol A - Google Patents

Synthesis method of euphorbiaceae diterpene Pepluanol A Download PDF

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CN114560760B
CN114560760B CN202210105174.9A CN202210105174A CN114560760B CN 114560760 B CN114560760 B CN 114560760B CN 202210105174 A CN202210105174 A CN 202210105174A CN 114560760 B CN114560760 B CN 114560760B
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宣军
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ZJU Hangzhou Global Scientific and Technological Innovation Center
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Abstract

The invention discloses a method for synthesizing euphorbiaceae diterpenoid Pepluanol A, which belongs to the field of organic synthesis, wherein a key tricyclic skeleton is constructed by using a cycloheptenone derivative 2 as a reaction raw material through key steps such as Negishi coupling reaction, diels-Alder reaction, titanium free radical catalyzed serial cyclization reaction and the like, and finally, a target product euphorbiaceae diterpenoid Pepluanol A is obtained through the conversion of a later functional group. The synthesis method of the invention has simple operation, the 17-step synthesis is carried out to obtain the product, the condition is mild, and the total yield reaches 2.5% by controlling the reaction condition. The synthetic route of the invention has novel design thought, low cost and easy obtainment of raw materials, strong compatibility of each important functional group, and convenience for synthesizing various derivatives of the ingesta diterpenoid structure containing the same 5/6/7 condensed ring skeleton, thus laying a foundation for researching the structure-activity relationship of the compounds.

Description

Synthesis method of euphorbiaceae diterpene Pepluanol A
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing diterpene Pepluanol A in Euphorbiaceae.
Background
Natural products play an important role in the development of human society as valuable wealth of nature. Drug development based on natural products has been a major issue in drug development. Statistics show that more than half of the new clinical drugs approved by the FDA over the years are derived from natural products or derivatives thereof. The Chinese medicine has rich natural product resources and long-term Chinese medicine theory, and the combination of the natural product resources and the long-term Chinese medicine theory has great significance for developing new medicines with independent intellectual property rights.
Medicinal plants from the family Euphorbiaceae are used in traditional Chinese medicine for treating asthma, psoriasis and other diseases, wherein natural products of the family Euphorbiaceae often play an important active role. Due to the diversity of natural product structures and biological activities of euphorbiaceae plants, it is often the main source route for the discovery of natural drugs. However, the amount of natural products obtained by separation is usually small and cannot be prepared in large quantities, so that the total synthesis of the natural products becomes an important intermediate link between the discovery of active ingredients and the research of pharmaceutical chemistry.
Diterpenoid compounds are natural products with complex and various structures and important biological activities, new strategies and new methods are designed and developed to realize simple and efficient synthesis, and the diterpenoid compounds have important scientific and practical significance for promoting the development of new methods and new theories of organic synthesis and the discovery of new drugs, and the synthesis methods of partial diterpenoid compounds are reported in the prior art, such as: the Chinese patent document with publication number CN108503652A discloses a chemical total synthesis preparation method of crotonane diterpene Prostratin, which is characterized in that 5- (hydroxymethyl) -2-cyclopentene-1-alcohol which is easy to prepare is used as a raw material, and is subjected to key reactions such as photo-oxidation dearomatization, intramolecular induced addition reaction, olefin metathesis reaction and the like, and finally functional group conversion to obtain a target product.
The Chinese patent document with publication number CN105152992A discloses a synthetic method of a cyclopiane tetracyclic diterpenoid natural product (conidiogenoneB, conidiogenone and conidiogenol), which is characterized in that an intermediate with conjugated ketene and cyclobutanol structures is synthesized from known conjugated ester, then a rearrangement reaction is performed under the action of acid to construct a tetracyclic framework structure of the tetracyclic diterpenoid, then the tetracyclic framework structure of the tetracyclic diterpenoid is constructed through structural modification and cyclization reaction under the action of acid, and then the tetracyclic diterpenoid framework is used as a key intermediate to synthesize the cyclopiane tetracyclic diterpenoid natural product through multi-step chemical conversion.
The euphorbiaceae diterpene Pepluanol A is originally separated from an acetone extract of Euphorbia peplus, the compound has a [5,4,7,3] tetracyclic skeleton, contains 7 chiral centers, wherein 6 continuous chiral centers and one quaternary carbon form a highly compact condensed ring skeleton, the synthesis is difficult, and the compound shows biological activity of blocking Kv1.3 potassium ion channels, and can be used for potentially treating some T cell mediated immune diseases such as type I diabetes mellitus, asthma and the like.
Disclosure of Invention
The invention provides a method for synthesizing euphorbiaceae diterpene Pepluanol A, which is characterized by controllable reaction sites in each step from racemization raw materials, and high total yield which reaches 2.5 percent. Realizes 17-step complete synthesis of the euphorbiaceae diterpene Pepluanol A, and lays a foundation for further researching the structure-activity relationship of the euphorbiaceae diterpene compounds.
The technical scheme adopted is as follows:
a method for synthesizing diterpene Pepluanol A of Euphorbiaceae comprises the following steps:
Step 1: dissolving an enone compound 2 in an organic solvent, adding azido trimethylsilane, an iodizing reagent and organic alkali, and reacting to obtain an alkenyl iodide compound 3;
Step 2: dissolving an alkenyl iodine compound 3 in an organic solvent, adding an organic phosphine, a metal palladium catalyst and an organic zinc reagent, and reacting to obtain an ketene compound 4;
Step 3: mixing the ketene compound 4 with a conjugated diene ether compound, reacting to obtain a mixture, dissolving the mixture with an organic solvent, adding hydrochloric acid, and further reacting to obtain a diketone compound 6;
Step 4: dissolving a diketone compound 6 in an organic solvent, adding a trifluoromethanesulfonyl reagent and strong alkali, and reacting to obtain a trifluoromethanesulfonate compound 7;
Step 5: dissolving a trifluoromethane sulfonate compound 7 in an organic solvent, adding a metal copper catalyst and a methyl metal reagent, and reacting to obtain a conjugated diene compound 8;
Step 6: dissolving the conjugated diene compound 8 in an organic solvent, adding inorganic base, and reacting to obtain a hemiketal compound 9;
Step 7: dissolving a hemiketal compound 9 in an organic solvent, adding water, inorganic base and a peroxidation reagent, and reacting to obtain an epoxy compound 10;
Step 8: dissolving an epoxy compound 10 in an organic solvent, adding organic phosphine and an azodicarbonate compound, and reacting to obtain a triene compound 11;
Step 9: dissolving a triene compound 11 in an organic solvent, adding water, organic base, catalytic amount of oxidant and equivalent oxidant, and reacting to obtain an aldehyde compound 12;
Step 10: mixing an organic metal titanium reagent with reduced metal, adding organic alkali hydrochloride and an aldehyde compound 12, and reacting to obtain a diol compound 13;
step 11: dissolving a diol compound 13 in an organic halogenated solvent, adding a phase transfer catalyst and inorganic strong base, and reacting to obtain a cyclopropane compound 14;
Step 12: reacting the cyclopropane compound 14, methyl iodide, a methyl metal reagent and an organic base to obtain a gem-dimethyl cyclopropane compound 15;
Step 13: dissolving the gem-dimethyl cyclopropane compound 15 in a mixed solvent, and then adding a nitrogen oxide, a phase transfer catalyst, inorganic base and an oxidant to react to obtain a gem-dimethyl diketone compound 16;
Step 14: dissolving the gem-dimethyl diketone compound 16 in an organic solvent, adding organic base and a silicon-based reagent, and reacting to obtain a gem-dimethyl silicone ether compound 17;
Step 15: dissolving the gem-dimethyl silicone ether compound 17 in an organic solvent, adding a metal palladium catalyst, and reacting to obtain a gem-dimethyl ketene compound 18;
Step 16: dissolving the gem-dimethyl ketene compound 18 in an organic solvent, adding a methyl metal reagent, and reacting to obtain a gem-dimethyl allyl alcohol compound 19;
Step 17: dissolving geminal dimethylallyl alcohol compound 19 in an organic solvent, adding silica gel, inorganic salt and oxidant, stirring, adding hydrochloric acid, and continuing stirring to obtain Euphorbiaceae diterpene Pepluanol A with a structure shown in formula I;
Preferably, in step 1, the iodination reagent is elemental iodine or N-iodosuccinimide; the organic base is pyridine, triethylamine, 4-dimethylaminopyridine or 1, 4-diazabicyclo [2.2.2] octane; the molar ratio of the ketene compound 2, the organic base, the iodinating agent and the azido trimethylsilane is 1:4 to 5:1 to 1.5:1 to 1.5; the ratio of the ketene compound 2 to the organic solvent is 1mmol: 1-5 mL.
Preferably, in step 2, the organic phosphine is tris (2-furyl) phosphine, triphenylphosphine or tributylphosphine; the metal palladium catalyst is bis (dibenzylidene) palladium acetonate, palladium acetate, tetra (triphenylphosphine) palladium, palladium chloride or bis (acetonitrile) palladium dichloride; the organic zinc reagent is 3-butenyl zinc bromide; the ratio of the alkenyl iodine compound 3 to the organic solvent is 1mmol: 3-5 mL; the molar ratio of the alkenyl iodine compound 3 to the organic zinc reagent to the organic phosphine to the metal palladium catalyst is 1:1.0 to 1.5:0.1 to 0.5:0.05 to 0.1.
Preferably, in step 3, the conjugated diene ether compound is Rawal diene; the molar ratio of the ketene compound 4 to the conjugated diene ether compound is 1:1.5 to 2.
Preferably, in step 4, the strong base is potassium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, or lithium diisopropylamide; the trifluoromethanesulfonyl reagent is N-phenyl bis (trifluoromethanesulfonyl) imine, 2- [ N, N-bis (trifluoromethanesulfonyl) amino ] -5-chloropyridine or trifluoromethanesulfonyl anhydride; the ratio of the diketone compound 6 to the organic solvent is 1mmol: 5-10 mL; the molar ratio of diketone compound 6, strong base and trifluoromethanesulfonyl reagent is 1:1.1 to 1.5:1.1 to 1.5.
Preferably, in step 5, the metallic copper catalyst is cuprous iodide, cuprous bromide or cuprous dimethyl sulfide bromide; the methyl metal reagent is methyl magnesium bromide, trimethylaluminum, methyl magnesium iodide or methyl lithium; the proportion of the triflate compound 7 to the organic solvent is 1mmol: 5-10 mL; the molar ratio of the triflate compound 7, the metallic copper catalyst and the methyl metal reagent is 1:0.05 to 0.1:1.5 to 2.
Preferably, in step 6, the inorganic base is sodium ethoxide, potassium carbonate, sodium methoxide, potassium tert-butoxide or sodium tert-butoxide; the molar ratio of the conjugated diene compound 8 to the inorganic base is 1:3, a step of; the ratio of the conjugated diene compound 8 to the organic solvent is 1mmol: 5-10 mL.
Preferably, in step 7, the inorganic base is sodium bicarbonate, potassium bicarbonate or sodium acetate; the peroxidation reagent is potassium peroxomonosulphonate, hydrogen peroxide, m-chloroperoxybenzoic acid or peroxyacetone; the proportion of the hemiketal compound 9 to the organic solvent is 1mmol: 5-10 mL; the mole ratio of the hemiketal compound 9, the inorganic base and the peroxidation agent is 1: 5-10: 1 to 5.
Preferably, in step 8, the organic phosphine is tris (2-furyl) phosphine, triphenylphosphine or tributylphosphine; the azodicarboxylic acid ester compound is diethyl azodicarboxylate or diisopropyl azodicarboxylate; the ratio of the epoxy compound 10 to the organic solvent is 1mmol: 10-15 mL; the molar ratio of the epoxy compound 10 to the organic phosphine to the azodicarboxylic acid compound is 1:2 to 4:2 to 4.
Preferably, in step 9, the organic base is 2, 6-lutidine, pyridine or tetramethyl ethylenediamine; the catalytic amount of oxidant is osmium tetroxide or potassium osmium oxide; the equivalent oxidant is periodic acid or sodium periodate; the ratio of the triene compound 11 to the organic solvent is 1mmol: 12-17 mL; the mole ratio of the triene compound 11, the organic base, the catalytic amount of oxidant and the equivalent oxidant is 1:1 to 3:0.05 to 0.15:3 to 5.
Preferably, in step 10, the organometallic titanium reagent is titanocene dichloride; the reduction metal is zinc powder or manganese powder; the organic base hydrochloride is 2,4, 6-trimethyl pyridine hydrochloride; the molar ratio of the aldehyde compound 12, the reducing metal, the organic metal titanium reagent and the organic base hydrochloride is 1:1 to 5:1:1.
Preferably, in step 11, the phase transfer catalyst is benzyl triethyl ammonium chloride, tetrabutyl ammonium bromide or tetrabutyl ammonium iodide; the inorganic strong base is potassium tert-butoxide, sodium hydroxide or potassium hydroxide; the proportion of the diol compound 13 and the organic halogenated solvent is 1mmol: 20-50 mL; the mass ratio of the diol compound 13 to the phase transfer catalyst to the inorganic strong base is 1:0.05 to 0.1:50.
Preferably, in step 12, the methyl metal reagent is methyl lithium or methyl copper lithium; the organic base is hexamethylphosphoric triamide or N, N-dimethyl propenyl urea; the molar ratio of the cyclopropane compound 14, the methyl metal reagent, the methyl iodide and the organic base is 1: 30-50: 30-50: 5 to 20.
Preferably, in step 13, the inorganic base is sodium bicarbonate, potassium bicarbonate or sodium acetate; the phase transfer catalyst is benzyl triethyl ammonium chloride, tetrabutyl ammonium bromide or tetrabutyl ammonium iodide; the oxidant is chlorosuccinimide, sodium hypochlorite or iodobenzene acetate; the nitrogen oxide is tetramethyl piperidine nitrogen oxide or 2-aza adamantane-N-oxygen free radical; the proportion of the gem-dimethylcyclopropane compound 15 and the mixed solvent is 1mmol: 100-150 mL; the mass ratio of the materials of the geminal dimethylcyclopropane compound 15, the inorganic base, the phase transfer catalyst, the oxidant and the nitrogen oxide is 1:4 to 6:1:1 to 3:0.05 to 0.2.
Preferably, in step 14, the organic base is triethylamine, 2, 6-lutidine or pyridine; the silicon-based reagent is trimethyl silyl triflate, triethyl silyl triflate or tertiary butyl disilyl trifluoro methyl sulfonate; the proportion of the gem-dimethyl diketone compound 16 and the organic solvent is 1mmol: 50-100 mL; the molar ratio of the geminal dimethyl diketone compound 16, the organic base and the silicon-based reagent is 1: 5-10: 2 to 5.
Preferably, in step 15, the metal palladium catalyst is palladium acetate or palladium trifluoroacetate; the proportion of the geminal dimethyl silicone ether compound 17 and the organic solvent is 1mmol: 50-100 mL; the molar ratio of the geminal dimethyl silicon ether compound 17 to the metal palladium catalyst is 1:1.5 to 3.
Preferably, in step 16, the methyl metal reagent is methyl magnesium bromide, methyl magnesium iodide, trimethylaluminum or methyl lithium; the proportion of the gem-dimethyl ketene compound 18 and the organic solvent is 1mmol: 50-100 mL; the molar ratio of the geminal dimethylketene compound 18 to the methyl metal reagent is 1:1 to 5.
Preferably, in step 17, the inorganic salt is sodium acetate or sodium bicarbonate; the oxidant is pyridinium chlorochromate or pyridinium dichromate; the proportion of the gem-dimethylallyl alcohol compound 19 and the organic solvent is 1mmol: 50-100 mL; the mass ratio of the geminal dimethylallyl alcohol compound 19 to the silica gel to the inorganic salt to the oxidant is 1:1 to 1.5:0.5 to 1:0.5 to 1.
Further preferably, in step 10, the reducing metal is manganese powder; in the step 12, the organic base is N, N-dimethyl propenyl urea; the manganese powder and the N, N-dimethyl propenyl urea can be selected to ensure the yield and improve the operation safety; in the step 15, the metal palladium catalyst is palladium trifluoroacetate, the yield can reach 95% by selecting the conditions, and the strong electron-withdrawing characteristic of trifluoro can enable trifluoroacetate anions to have stronger alkalinity, so that the beta hydrogen elimination of palladium is more efficient. Chemoselectivity and stereoselectivity have been key factors in the development of fine organic synthesis, and the site selectivity of the reaction has a close and inseparable relationship with yield and the nature of the catalyst, ligand, substrate itself, etc.
Compared with the prior art, the invention has the beneficial effects that:
(1) The synthesis route adopted by the invention is to construct a key tricyclic skeleton by taking easily-prepared cycloheptenone derivatives as a starting raw material through key steps such as Negishi coupling reaction, diels-Alder reaction, titanium free radical catalyzed serial cyclization reaction and the like, and finally obtain the target product Euphorbiaceae diterpene Pepluanol A through the conversion of a later functional group.
(2) The synthesis method of the invention has simple operation, the 17-step synthesis method is used for obtaining the product, the condition is mild, and the total yield reaches 2.5%. The synthesized product is consistent with the NMR spectrum data of the natural product.
(3) The synthetic route of the invention has novel design thought, low cost and easy obtainment of raw materials, strong compatibility of each important functional group, and convenience for synthesizing various derivatives of the ingesta diterpenoid structure containing the same 5/6/7 condensed ring skeleton, thus laying a foundation for researching the structure-activity relationship of the compounds.
Drawings
FIG. 1 is a synthetic route diagram of the Euphorbiaceae diterpene Pepluanol A compounds of the present invention.
FIG. 2 is a hydrogen spectrum of the Euphorbiaceae diterpene Pepluanol A compound of the present invention.
FIG. 3 is a carbon spectrum of the Euphorbiaceae diterpene Pepluanol A compound of the present invention.
Detailed Description
The invention is further elucidated below in connection with the drawings and the examples. It is to be understood that these examples are for illustration of the invention only and are not intended to limit the scope of the invention.
Example 1
The synthetic route for Pepluanol A compounds is shown in figure 1.
Step 1:
To a solution of (20 g,0.082 mol) of ketene compound 2 in methylene chloride (200 mL) was added azido trimethylsilane (11.9 mL,0.09 mol) at 0℃and stirred for 2 hours, then elemental iodine (22.86 g,0.09 mol) and pyridine (26.5 mL,0.33 mol) were added in this order, the mixture was slowly warmed to room temperature and stirred for 24 hours, the reaction was quenched with 50mL of saturated ammonium chloride solution, extracted with methylene chloride, washed with saturated brine and dried over anhydrous sodium sulfate, and the purified product was isolated by silica gel column chromatography to give a pale yellow oil, namely alkenyl iodide 3 (26.7 g, 88%).
Nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ＝8.06(dd,J＝8.2,1.1Hz,2H),7.65–7.56(m,1H),7.53(dd,J＝2.8,1.1Hz,1H),7.50–7.44(m,2H),5.78(dt,J＝10.2,2.9Hz,1H),2.94–2.84(m,1H),2.28–2.21(m,1H),1.99(ddddd,J＝20.2,16.9,13.3,9.9,6.7Hz,2H),1.64–1.52(m,1H),1.23ppm(d,J＝6.5Hz,3H).
13C NMR(100MHz,CDCl3)δ＝198.8,165.4,153.8,133.5,129.8(2C),129.4,128.6(2C),105.6,73.3,43.8,31.3,27.0,17.3ppm.
High resolution mass spectrometry data:
HRMS(ESI):calcd for C15H16IO3 +[M+H]+371.0139,found 371.0137。
step 2:
To a solution of anhydrous zinc chloride (8.08 g,59.4 mmol) in tetrahydrofuran (100 mL) was slowly added 3-butenyl magnesium bromide (0.5M in tetrahydrofuran, 118.8mL,59.4 mmol) at-78deg.C, and the mixture was slowly warmed to 0deg.C to give 3-butenyl zinc bromide reagent ready for use.
To a solution of alkenyl iodide 3 (20 g,54.0 mmol) in N, N-dimethylformamide (200 mL) were successively added tris (2-furyl) phosphine (3.1 g,5.4 mmol) and bis (dibenzylideneacetone palladium (626.4 mg,2.7 mmol), the mixture was stirred for 10min, then the above 3-butenyl zinc bromide reagent (220 mL,0.054 mol) was slowly added dropwise, after stirring for 1 hour, the reaction was quenched with 50mL saturated ammonium chloride, extracted with diethyl ether, washed with saturated brine and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the purified product was isolated by silica gel column chromatography to give a pale yellow oily substance, namely, ketene compound 4 (11.9 g, 74%).
Nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ＝8.10–8.03(m,2H),7.61–7.53(m,1H),7.50–7.39(m,2H),6.38(dd,J＝2.5,1.2Hz,1H),5.84–5.67(m,2H),5.02–4.90(m,2H),2.79–2.65(m,1H),2.50(ddt,J＝15.1,8.2,1.2Hz,1H),2.29(ddt,J＝12.3,11.3,5.8Hz,1H),2.25–2.11(m,3H),2.00–1.77(m,2H),1.54–1.42(m,1H),1.14ppm(d,J＝6.5Hz,3H).
13C NMR(100MHz,CDCl3)δ＝205.1,165.7,143.1,140.2,137.7,133.2,130.0,129.7(2C),128.4(2C),115.3,72.2,45.5,33.1,32.8,31.8,27.1,16.5ppm.
High resolution mass spectrometry data:
HRMS(ESI):calcd for C19H23O3 +[M+H]+299.1642,found 299.1642。
Step 3:
Rawal diene 5 (13.3 mL,51 mmol) was added to ketene compound 4 (10 g,34 mmol) of the above formula, the reaction solution was stirred at 40℃for 24 hours, the resulting mixture was dissolved in tetrahydrofuran (200 mL), cooled to-30℃and then hydrochloric acid (2M aqueous solution, 68mL,136 mol) was slowly added dropwise, the mixture was slowly warmed to room temperature and stirred for 24 hours, 100mL of saturated sodium hydrogencarbonate was quenched for reaction, ethyl acetate was extracted, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the purified product was isolated by silica gel column chromatography to give a white powdery solid, namely diketone compound 6 (10.3 g, 83%).
Nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ＝7.96(dd,J＝5.1,3.3Hz,2H),7.61–7.53(m,1H),7.43(dd,J＝10.7,4.7Hz,2H),6.80(d,J＝10.3Hz,1H),6.21(d,J＝10.3Hz,1H),5.73–5.60(m,1H),5.26–5.17(m,1H),4.97–4.85(m,2H),2.99(dp,J＝8.7,6.5Hz,1H),2.73(dt,J＝5.8,4.2Hz,1H),2.69–2.57(m,2H),2.31(dt,J＝10.3,8.0Hz,1H),2.04–1.90(m,4H),1.90–1.73(m,2H),1.60(ddd,J＝14.5,9.1,4.6Hz,1H),1.15ppm(d,J＝6.6Hz,3H).
13C NMR(100MHz,CDCl3)δ＝211.9,196.5,165.4,150.7,137.7,133.3,123.0,129.7,129.7(2C),128.5(2C),115.3,75.2,55.5,44.5,43.3,38.6,37.2,29.1,29.0,27.6,17.3ppm.
High resolution mass spectrometry data:
HRMS(ESI):calcd for C23H27O4 +[M+H]+367.1904,found 367.1905。
Step 4:
To a solution of diketone compound 6 (11.94 g,33.9 mmol) of the above formula (200 mL) was added N-phenylbis (trifluoromethanesulfonyl) imide (13.33 g,37.3 mmol), the mixture was cooled to-78℃and potassium bis (trimethylsilyl) amide (1M in tetrahydrofuran, 37.3mL,37.3 mmol) was slowly added dropwise, and the mixture was slowly warmed to room temperature and stirred for 1 hour, quenched with 50mL of saturated ammonium chloride, extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the purified product was isolated by silica gel column chromatography to give a pale yellow oil, i.e., trifluoromethanesulfonate compound 7 (15.6 g,29.5 mmol).
Step 5:
To a solution of trifluoromethane sulfonate 7 (15.6 g,29.5 mmol) of the above formula in tetrahydrofuran (200 mL) was added cuprous iodide (280 mg,1.48 mmol), the mixture was cooled to 0℃and methylmagnesium bromide (3M diethyl ether solution, 19.7mL,59 mmol) was slowly added dropwise, the reaction mixture was stirred for 3 hours, 50mL of saturated ammonium chloride was quenched, extracted with diethyl ether, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the purified product was isolated by silica gel column chromatography to give a pale yellow oil as conjugated diene compound 8 (8.9 g, yield of steps 4 and 5 was 72% in total).
Nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ＝8.01–7.92(m,2H),7.54(t,J＝7.4Hz,1H),7.45(t,J＝7.5Hz,2H),5.91(d,J＝10.3Hz,1H),5.77–5.61(m,1H),5.44(t,J＝5.7Hz,1H),5.23(d,J＝9.6Hz,2H),4.86(ddd,J＝13.7,11.4,1.4Hz,2H),3.13–3.01(m,2H),2.11–1.88(m,5H),1.82(s,3H),1.63–1.47(m,2H),1.45–1.34(m,1H),1.08ppm(d,J＝6.6Hz,3H).
13C NMR(100MHz,CDCl3)δ＝212.5,165.6,138.8,133.1,129.9,129.8(2C),129.6,128.5(2C),128.1,127.9,120.2,114.2,75.5,54.2,43.9,42.0,37.7,29.3,28.1,27.9,21.6,17.8ppm.
High resolution mass spectrometry data:
HRMS(ESI):calcd for C24H29O3 +[M+H]+365.2111,found 365.2114。
Step 6:
Sodium methoxide (4.5 g,82.5 mmol) was added in portions to a solution of conjugated diene compound 8 (10 g,27.5 mmol) of methanol (200 mL) of the above formula, the reaction mixture was stirred under reflux for 8 hours, quenched with 50mL of saturated ammonium chloride, extracted with diethyl ether, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the purified product was isolated by silica gel column chromatography to give a pale yellow oil, which was hemiketal compound 9 (5.9 g,22.8 mmol).
Step 7:
the hemiketal compound 9 (5.9 g,22.8 mmol) represented by the above formula was dissolved in a solution of acetone (120 mL), water (30 mL), sodium hydrogencarbonate (9.6 g,114 mmol) and potassium peroxymonosulfonate (21 g,68.4 mmol) were sequentially added, the reaction mixture was stirred for 1 hour, 100mL of saturated sodium hydrogencarbonate was quenched, extracted with diethyl ether, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the purified product was isolated by silica gel column chromatography to give a pale yellow oil as epoxy compound 10 (4.4 g, 58% of the total yield of steps 6 and 7).
Nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ＝5.84(d,J＝10.3Hz,1H),5.82–5.72(m,1H),5.56(d,J＝10.4Hz,1H),5.03–4.95(m,1H),4.94–4.88(m,1H),4.44(dd,J＝8.3,2.5Hz,1H),2.98(s,1H),2.86(d,J＝8.3Hz,1H),2.82(s,1H),1.97(ddd,J＝11.9,8.9,2.5Hz,2H),1.87–1.74(m,2H),1.69–1.56(m,5H),1.45(s,3H),1.00ppm(d,J＝7.3Hz,3H).
13C NMR(100MHz,CDCl3)δ＝139.0,133.2,126.3,114.3,106.0,74.4,57.6,52.7,48.4,43.7,42.7,36.4,28.1,27.5,25.5,21.1,15.8ppm.
High resolution mass spectrometry data:
HRMS(ESI):calcd for C17H25O3 +[M+H]+277.1798,found 277.1796。
Step 8:
triphenylphosphine (3.8 g,14.4 mmol) and diethyl azodicarboxylate (2.2 mL,14.4 mmol) were added sequentially to a solution of epoxy compound 10 (1 g,3.6 mmol) of the above formula in tetrahydrofuran (50 mL), the reaction mixture was stirred at 60℃for 1 hour, 25mL of saturated sodium hydrogencarbonate was used for quenching reaction, diethyl ether was used for extraction, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the purified product was isolated by silica gel column chromatography to give a pale yellow oily substance, namely triene compound 11 (622 mg, 67%).
Nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ＝6.44(d,J＝10.4Hz,1H),5.91(d,J＝10.4Hz,1H),5.67(ddt,J＝16.9,10.2,6.6Hz,1H),5.57–5.47(m,1H),5.21(dddd,J＝11.6,4.5,2.6,1.7Hz,1H),4.98–4.81(m,2H),3.66(dp,J＝12.6,6.3Hz,1H),3.56(s,1H),3.41(d,J＝3.0Hz,1H),2.47(ddq,J＝18.1,5.8,2.8Hz,1H),2.35–2.20(m,1H),2.08–1.86(m,2H),1.67(ddd,J＝16.6,10.3,4.4Hz,2H),1.52(s,3H),1.10(d,J＝6.4Hz,3H).
13C NMR(100MHz,CDCl3)δ＝211.6,138.0,131.8,130.6,127.7,127.6,114.6,66.0,59.2,52.6,40.9,38.1,37.7,36.4,29.2,21.4,16.8ppm.
High resolution mass spectrometry data:
HRMS(ESI):calcd for C17H23O2 +[M+H]+259.1693,found 259.1697。
Step 9:
Water (10 mL), 2, 6-lutidine (450. Mu.L, 3.88 mmol), osmium tetroxide (2% by mass aqueous solution, 2.54mL,0.2 mmol) and sodium periodate (1.67 g,7.76 mmol) were added sequentially to a solution of triene compound 11 (500 mg,1.94 mmol) shown by the above formula in 1, 4-dioxane (30 mL), the mixture was stirred for 3 hours, the reaction was quenched with 25mL saturated sodium thiosulfate, extracted with methylene chloride, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the product was isolated and purified by silica gel column chromatography to give a pale yellow oil as aldehyde compound 12 (353 mg, 70%).
Nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ＝9.63(t,J＝1.2Hz,1H),6.36(dd,J＝10.4,0.8Hz,1H),5.96(d,J＝10.4Hz,1H),5.59–5.48(m,1H),5.26–5.16(m,1H),3.69(dt,J＝18.4,6.2Hz,1H),3.62(s,1H),3.44(d,J＝3.1Hz,1H),2.55–2.43(m,2H),2.42–2.30(m,1H),2.19–2.07(m,1H),2.01–1.89(m,2H),1.52(s,3H),1.08(d,J＝6.4Hz,3H).
13C NMR(100MHz,CDCl3)δ＝211.2,201.2,130.8,130.6,129.0,127.4,65.91,58.3,52.5,39.3,38.2,37.6,36.1,32.6,21.3,16.8ppm.
High resolution mass spectrometry data:
HRMS(ESI):calcd for C16H21O3 +[M+H]+261.1485,found 261.1482。
Step 10:
Titanocene dichloride (191 mg,0.77 mmol) and manganese powder (170 mg,3.08 mmol) were dissolved in tetrahydrofuran (25 mL), and after intense stirring for 10 minutes, the solution turned green, 2,4, 6-trimethylpyridine hydrochloride (151 mg,0.77 mmol) was added, followed by stirring for 5 minutes, then a solution of aldehyde compound 12 (200 mg,0.77 mmol) of the formula shown in the formula (II) in tetrahydrofuran (15 mL) was slowly added dropwise over 1 hour, the reaction solution was stirred for 2 hours, diatomite was filtered, the filtrate was concentrated under reduced pressure, and the purified product was isolated by silica gel column chromatography to give a white powdery solid, namely diol compound 13 (199mg, 99%, diastereomer ratio 1:1).
Nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ＝5.60(d,J＝5.4Hz,2H),5.53–5.43(m,2H),5.18–4.98(m,2H),4.31(s,1H),4.22–4.13(m,1H),4.05(d,J＝7.1Hz,1H),3.93(dd,J＝13.2,3.6Hz,2H),3.82–3.70(m,2H),3.61(dt,J＝12.1,6.0Hz,1H),3.53(t,J＝5.1Hz,2H),3.45(d,J＝2.0Hz,1H),2.85(s,1H),2.69–2.55(m,2H),2.51–2.35(m,2H),2.15(s,1H),2.11–1.94(m,3H),1.94–1.90(m,3H),1.85(d,J＝4.6Hz,1H),1.84–1.81(m,4H),1.81–1.70(m,3H),1.59–1.46(m,2H),1.34–1.26(m,1H),1.18–1.09(m,6H).
13C NMR(100MHz,CDCl3)δ＝218.6,212.0,139.4,131.7,131.3,131.1,129.2,128.8,127.5,123.2,79.4,75.0,74.1,73.2,62.2,62.2,48.5,43.8,42.6,42.5,39.6,39.1,37.4,37.2,34.3,33.7,33.2,32.0,22.6,21.5,17.5,17.4ppm.
High resolution mass spectrometry data:
HRMS(ESI):calcd for C16H23O3 +[M+H]+263.1642,found 263.1644。
Step 11:
Benzyl triethyl ammonium chloride (4.3 mg) and sodium hydroxide (50% by mass aqueous solution, 5 mL) were added sequentially to a solution of diol compound 13 (50 mg,0.19mmol, diastereomer ratio 1:1) of the above formula, the reaction mixture was stirred at 50℃for 2 hours, quenched with 10mL saturated ammonium chloride solution at 0℃for reaction, extracted with methylene chloride, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the purified product was separated by silica gel column chromatography to give a pale yellow oily substance, namely cyclopropane compound 14.
Step 12:
A new dried solution of cuprous thiocyanate (413 mg,3.4 mmol) in diethyl ether (30 mL) was cooled to-78℃and then methyllithium (1.6M diethyl ether solution, 4.3mL,6.8 mmol) was slowly added dropwise, the reaction solution was slowly warmed to-20℃and a solution of cyclopropane compound 14 (71 mg,0.17 mmol) and N, N-dimethyl propenyl urea (217. Mu.L, 1.7 mmol) as indicated above in the above formula in diethyl ether (15 mL) was slowly added dropwise, after stirring for 1 hour, methyl iodide (414. Mu.L, 6.8 mmol) was added, the reaction solution was continued to stir for 30min, and 20mL saturated ammonium chloride was quenched, extracted with diethyl ether, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the purified product was isolated by silica gel column chromatography to give a pale yellow oil as a geminal dimethylcyclopropane compound 15 (25 mg; the total yield of steps 11 and 12: 44%, diastereomer ratio 1:1).
Diastereomer 1 nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ＝5.53(d,J＝1.6Hz,1H),4.13–4.04(m,1H),4.02(d,J＝9.0Hz,1H),3.89(d,J＝4.7Hz,1H),3.23–3.11(m,1H),3.01(s,1H),2.42–2.35(m,1H),2.32(d,J＝12.8Hz,1H),2.02–1.86(m,2H),1.83(s,3H),1.79–1.65(m,3H),1.49–1.39(m,1H),1.12(s,3H),1.09(d,J＝6.3Hz,3H),0.96(s,3H),0.59(td,J＝9.5,4.3Hz,1H),0.33(dd,J＝11.9,9.3Hz,1H).
13C NMR(100MHz,CDCl3)δ＝219.5,131.1,126.2,79.6,73.8,60.7,47.5,41.1,38.7,33.4,32.2,30.7,29.7,28.8,21.7,21.5,18.4,18.1,15.0ppm.
diastereomer 1 high resolution mass spectrometry data:
HRMS(ESI):calcd for C19H29O3 +[M+H]+305.2111,found 305.2115。
Diastereomer 2 nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ＝5.64(d,J＝4.9Hz,1H),4.33(s,1H),3.84(d,J＝6.8Hz,1H),3.61(d,J＝5.0Hz,1H),3.32(d,J＝8.5Hz,1H),3.18–3.05(m,1H),2.59–2.44(m,1H),2.29(dd,J＝11.6,2.0Hz,1H),1.90(s,4H),1.88–1.78(m,2H),1.68(ddd,J＝20.1,14.0,9.9Hz,4H),1.41(ddd,J＝22.9,15.0,9.0Hz,1H),1.08(t,J＝3.1Hz,6H),0.94(s,3H),0.56(ddd,J＝19.8,11.5,5.3Hz,1H),0.23ppm(dd,J＝11.4,9.5Hz,1H).
13C NMR(100MHz,CDCl3)δ＝213.1,138.1,122.2,75.0,74.4,59.6,42.5,41.8,40.3,33.4,32.0,30.0,28.9,28.9,22.9,22.7,18.3,17.9,14.8ppm.
diastereomer 2 high resolution mass spectrometry data:
HRMS(ESI):calcd for C19H29O3 +[M+H]+305.2111,found 305.2109。
Step 13:
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To a mixed solution of 15 (25 mg,0.082 mmol) of the gem-dimethylcyclopropane compound represented by the above formula (5 mL) and water (5 mL) were added successively tetramethyl piperidine oxide (2 mg,0.008 mmol), tetrabutyl ammonium chloride (23 mg,0.082 mmol), sodium hydrogencarbonate (35 mg,0.41 mmol) and chlorosuccinimide (22 mg,0.16 mmol), the reaction mixture was stirred for 2 hours, 10mL of saturated sodium hydrogencarbonate solution was quenched, extracted with dichloromethane, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the purified product was isolated by silica gel column chromatography to give a pale yellow oil, namely 16 (23.5 mg, 95%) as the gem-dimethyldiketone compound.
Nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ＝5.42(dd,J＝3.0,1.4Hz,1H),4.00(s,1H),3.25(s,1H),3.19(ddd,J＝10.6,8.1,6.5Hz,1H),2.77(ddd,J＝13.8,12.2,9.0Hz,1H),2.32(d,J＝11.6Hz,1H),2.18(dd,J＝18.8,8.8Hz,1H),2.11–1.99(m,1H),1.98–1.88(m,2H),1.88–1.86(m,3H),1.75(ddd,J＝20.3,14.6,9.6Hz,2H),1.15(s,3H),1.07(d,J＝6.4Hz,3H),0.99(s,3H),0.59(td,J＝9.4,4.1Hz,1H),0.33ppm(dd,J＝11.9,9.2Hz,1H).
13C NMR(100MHz,CDCl3)δ＝216.1,215.2,133.8,120.0,73.6,58.4,50.0,39.9,37.8,34.8,30.2,29.6,28.7,25.9,21.5,21.3,18.3,17.4,15.1ppm.
High resolution mass spectrometry data:
HRMS(ESI):calcd for C19H27O3 +[M+H]+303.1955,found 303.1956。
Step 14:
A solution of the gem-dimethyl-diketone compound 16 (20 mg,0.066 mmol) in methylene chloride (5 mL) was cooled to 0℃and triethylamine (91. Mu.L, 0.66 mmol) and trimethylsilyl triflate (48. Mu.L, 0.264 mmol) were slowly added in this order, the reaction mixture was stirred at 0℃for 30 minutes, the reaction was quenched with 10mL saturated sodium bicarbonate, extracted with methylene chloride, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the resultant was concentrated under reduced pressure to give gem-dimethyl-silyl compound 17 (25 mg).
Step 15:
The gem-dimethylsilyl ether compound 17 (25 mg,0.066 mmol) represented by the above formula was dissolved in acetonitrile (5 mL), palladium trifluoroacetate (43 mg,0.132 mmol) was added, the reaction solution was stirred for 3 hours, and then, silica gel was filtered, concentrated under reduced pressure, and the purified product was separated by silica gel column chromatography to obtain a white powdery solid, namely gem-dimethylsilenone compound 18 (23 mg, total yield of steps 14 and 15 was 95%).
Nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ＝7.38(d,J＝5.6Hz,1H),5.82(d,J＝5.6Hz,1H),5.59–5.42(m,1H),3.86(d,J＝2.4Hz,1H),3.66(dd,J＝4.4,1.9Hz,1H),3.13–2.97(m,1H),2.39(dd,J＝11.8,2.4Hz,1H),1.98–1.87(m,1H),1.82–1.75(m,1H),1.74(t,J＝1.6Hz,3H),1.15(s,3H),1.03(d,J＝6.4Hz,3H),0.99(s,3H),0.65(td,J＝9.3,4.9Hz,1H),0.44(dd,J＝11.7,9.3Hz,1H),0.14ppm(s,9H).
13C NMR(100MHz,CDCl3)δ＝209.7,207.9,162.6,133.3,128.7,120.7,73.1,66.0,48.6,42.3,40.4,28.9,28.2,27.9,21.7,21.4,18.2,17.0,15.1,0.0(3C)ppm.
High resolution mass spectrometry data:
HRMS(ESI):calcd for C22H33O3Si+[M+H]+373.2193,found 373.2194。
Step 16:
A toluene (4 mL) solution of the gem-dimethylenones 18 (15 mg,0.042 mmol) shown in the above formula was cooled to 0 ℃, methyl lithium (1.6M diethyl ether solution, 53. Mu.L, 0.084 mmol) was slowly added dropwise thereto, after stirring for 30min, the reaction was quenched with 10mL of saturated ammonium chloride solution, extracted with diethyl ether, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the purified product was isolated by silica gel column chromatography to give a pale yellow oil, namely gem-dimethylallylalcohols 19 (13 mg).
Step 17:
Silica gel (18 mg), sodium acetate (7 mg,0.084 mmol) and pyridinium chlorochromate (9 mg,0.084 mmol) were sequentially added to a solution of gem-dimethylallyl alcohol 19 (13 mg,0.042 mmol) shown in the above formula in methylene chloride (3 mL), the mixture was stirred for 30 minutes, then hydrochloric acid (2M aqueous solution, 84. Mu.L, 0.168 mmol) was added, the reaction was quenched with 2mL of saturated sodium bicarbonate, extracted with methylene chloride, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the purified product was isolated by silica gel column chromatography to give a white powdery solid as pepluanol A% (7.7 mg; overall yield of steps 16 and 17 was 59%).
The NMR hydrogen spectrum and NMR carbon spectrum of the product pepluanol A are shown in fig. 2 and 3, respectively, and the NMR spectrum data of the product synthesized by the method of the invention is consistent with that of the natural product.
Nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ＝5.77–5.70(brd,1H),5.69–5.65(brs,1H),3.96(brs,1H),3.92–3.86(brs,1H),3.56–3.44(m,1H),2.95(dd,J＝11.8,2.5Hz,1H),2.25(s,3H),2.01–1.92(m,1H),1.83(brs,3H),1.71(m,1H),1.52(d,J＝4.1Hz,1H),1.17(s,3H),0.98(s,3H),0.95(d,J＝6.4Hz,3H),0.61(td,J＝9.2,5.2Hz,1H),0.36ppm(dd,J＝11.8,9.3Hz,1H).
13C NMR(100MHz,CDCl3)δ＝207.3,203.4,181.8,134.6,125.1,122.7,73.6,71.7,46.6,41.7,39.3,29.2,28.8,28.4,22.5,22.3,18.8,18.3,17.6,14.9ppm.
High resolution mass spectrometry data:
HRMS(ESI):calcd for C20H27O3 +[M+H]+315.1955,found 315.1957。
While the foregoing embodiments have been described in detail in connection with the embodiments of the invention, it should be understood that the foregoing embodiments are merely illustrative of the invention and are not intended to limit the invention, and any modifications, additions, substitutions and the like made within the principles of the invention are intended to be included within the scope of the invention.

Claims (1)

1. A method for synthesizing euphorbiaceae diterpene Pepluanol A, comprising the steps of:
step 1:
Adding 0.09mol of azido trimethylsilane into 200mL of methylene dichloride solution of 0.082mol of ketene compound 2 at the temperature of 0 ℃, stirring for 2 hours, sequentially adding 0.09mol of elemental iodine and 0.33mol of pyridine, slowly heating the mixed solution to room temperature, stirring for 24 hours, quenching the mixed solution with 50mL of saturated ammonium chloride solution, extracting with methylene dichloride, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating and purifying the product by using a silica gel column chromatography to obtain light yellow oily matters, namely alkenyl iodine compound 3; the yield of step 1 was 88%;
step 2:
Slowly adding 118.8mL of 0.5M 3-butenyl magnesium bromide tetrahydrofuran solution into 59.4mmol of anhydrous zinc chloride 100mL of tetrahydrofuran solution at the temperature of minus 78 ℃, and slowly raising the temperature of the mixed solution to 0 ℃ to obtain a 3-butenyl zinc bromide reagent for later use;
sequentially adding 5.4mmol of tris (2-furyl) phosphine and 2.7mmol of dibenzylidene acetone palladium into 200mL of N, N-dimethylformamide solution of 54.0mmol of alkenyl iodine compound 3, stirring the mixed solution for 10min, slowly dropwise adding 0.054mol of the 3-butenyl zinc bromide reagent, stirring for 1h, quenching reaction by 50mL of saturated ammonium chloride, extracting by diethyl ether, washing by saturated saline solution, drying by anhydrous sodium sulfate, concentrating under reduced pressure, and separating and purifying the product by a silica gel column chromatography to obtain light yellow oily substance, namely the ketene compound 4; the yield of step 2 was 74%;
Step 3:
Adding 51mmol Rawal diene 5 into 34mmol of ketene compound 4 shown in the above formula, stirring the reaction solution at 40 ℃ for 24 hours, dissolving the obtained mixture in 200mL of tetrahydrofuran, cooling to-30 ℃, slowly dropwise adding 68mL of 2M hydrochloric acid aqueous solution, slowly heating the mixture to room temperature, stirring for 24 hours, quenching reaction by 100mL of saturated sodium bicarbonate, extracting by ethyl acetate, washing an organic layer by using saturated saline and drying by using anhydrous sodium sulfate, concentrating under reduced pressure, and separating and purifying the product by using a silica gel column chromatography to obtain white powdery solid, namely the diketone compound 6; the yield of step 3 was 83%;
Step 4:
Adding 37.3mmol of N-phenyl bis (trifluoromethanesulfonyl) imine into 200mL of tetrahydrofuran solution of diketone compound 6 shown in the above formula, cooling the mixed solution to-78 ℃, slowly dropwise adding 37.3mL of 1M tetrahydrofuran solution of bis (trimethylsilyl) aminopotassium, slowly heating to room temperature and stirring for 1 hour, quenching reaction by 50mL of saturated ammonium chloride, extracting by ethyl acetate, washing an organic layer by saturated saline solution and drying by anhydrous sodium sulfate, concentrating under reduced pressure, and separating and purifying the product by a silica gel column chromatography to obtain a light yellow oily substance, namely the trifluoromethanesulfonate compound 7;
Step 5:
Adding 1.48mmol of cuprous iodide into 200mL of tetrahydrofuran solution of a trifluoromethane sulfonate compound 7 shown in the above formula, cooling the mixed solution to 0 ℃, slowly dropwise adding 19.7mL of 3M methyl magnesium bromide diethyl ether solution, stirring the reaction solution for 3 hours, quenching the reaction by 50mL of saturated ammonium chloride, extracting the reaction solution by diethyl ether, washing an organic layer with saturated saline water, drying the organic layer by anhydrous sodium sulfate, concentrating the organic layer under reduced pressure, and separating and purifying the product by a silica gel column chromatography to obtain light yellow oily substance, namely the conjugated diene compound 8; the total yield of steps 4 and 5 was 72%;
Step 6:
82.5mmol of sodium methoxide is added to 200mL of a methanol solution of a conjugated diene compound 8 shown in the above formula in batches, the reaction solution is refluxed and stirred for 8 hours, 50mL of saturated ammonium chloride is used for quenching reaction, diethyl ether is used for extraction, an organic layer is washed by saturated saline water and dried by anhydrous sodium sulfate, the organic layer is concentrated under reduced pressure, and a light yellow oily substance is obtained by separating and purifying a product by a silica gel column chromatography, namely a hemiketal compound 9;
Step 7:
Dissolving 22.8mmol of hemiketal compound 9 shown in the above formula in 120mL of acetone solution, sequentially adding 30mL of water, 114mmol of sodium bicarbonate and 68.4mmol of potassium peroxymonosulfonate, stirring the reaction solution for 1 hour, quenching reaction by 100mL of saturated sodium bicarbonate, extracting by diethyl ether, washing an organic layer with saturated saline and drying by anhydrous sodium sulfate, concentrating under reduced pressure, and separating and purifying the product by a silica gel column chromatography to obtain light yellow oily substance, namely the epoxy compound 10; the total yield of steps 6 and 7 was 58%;
Step 8:
14.4mmol of triphenylphosphine and 14.4mmol of diethyl azodicarboxylate are sequentially added into 50mL of tetrahydrofuran solution of the epoxy compound 10 shown in the above formula, the reaction solution is stirred at 60 ℃ for 1 hour, 25mL of saturated sodium bicarbonate is used for quenching reaction, diethyl ether is used for extraction, an organic layer is washed by saturated saline and dried by anhydrous sodium sulfate, the organic layer is concentrated under reduced pressure, and a product is separated and purified by a silica gel column chromatography to obtain a light yellow oily substance, namely the triene compound 11; the yield of step 8 was 67%;
Step 9:
10mL of water, 450 mu L of 2, 6-lutidine, 2.54mL of 2% osmium tetroxide aqueous solution with mass fraction and 7.76mmol of sodium periodate are sequentially added into 30mL of 1, 4-dioxane solution of a triene compound 11 shown in the above formula, the mixed solution is stirred for 3 hours, 25mL of saturated sodium thiosulfate is used for quenching reaction, dichloromethane extraction is carried out, an organic layer is washed by saturated saline water and dried by anhydrous sodium sulfate, decompression concentration is carried out, and a light yellow oily matter is obtained by separating and purifying the product by a silica gel column chromatography, namely aldehyde compound 12; the yield of step 9 was 70%;
Step 10:
Dissolving 0.77mmol of titanocene dichloride and 3.08mmol of manganese powder in 25mL of tetrahydrofuran solution, vigorously stirring for 10 minutes, turning the solution green, adding 0.77mmol of 2,4, 6-trimethylpyridine hydrochloride, stirring for 5 minutes, slowly dropwise adding 0.77mmol of 15mL of tetrahydrofuran solution of aldehyde compound 12 shown in the formula in 1 hour, stirring the reaction solution for 2 hours, filtering by diatomite, concentrating the filtrate under reduced pressure, and separating and purifying the product by using a silica gel column chromatography to obtain white powdery solid, namely diol compound 13; the yield of step 10 was 99% with a diastereomer ratio of 1:1;
Step 11:
Adding 4.3mg of benzyl triethyl ammonium chloride and 5mL of 50% mass fraction sodium hydroxide aqueous solution into 0.19mmol of glycol compound 13 shown in the formula in sequence, stirring the reaction solution at 50 ℃ for 2 hours, quenching the reaction with 10mL of saturated ammonium chloride solution at 0 ℃, extracting with dichloromethane, washing an organic layer with saturated saline water, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating and purifying the product by a silica gel column chromatography to obtain light yellow oily substance, namely cyclopropane compound 14; the diastereoisomer ratio of the diol compound 13 is 1:1;
Step 12:
Cooling a newly dried 30mL diethyl ether solution of 3.4mmol of cuprous thiocyanate to-78 ℃, slowly dropwise adding 4.3mL of a 1.6M diethyl ether solution of methyllithium, slowly heating the reaction solution to-20 ℃, slowly dropwise adding 0.17mmol of cyclopropane compound 14 shown in the formula and 1.7mmol of 15mL of N, N-dimethyl propenyl urea into the reaction solution, stirring for 1 hour, adding 6.8mmol of methyl iodide, continuously stirring the reaction solution for 30min, quenching with 20mL of saturated ammonium chloride, extracting with diethyl ether, washing an organic layer with saturated saline and drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating and purifying a product by a silica gel column chromatography to obtain a light yellow oily substance, namely the gem-dimethyl cyclopropane compound 15; the overall yield of steps 11 and 12 was 44% with a diastereomer ratio of 1:1;
Step 13:
To a mixed solution of 5mL of dichloromethane and 5mL of water of a gem-dimethylcyclopropane compound 15 shown in the above formula, 0.008mmol of tetramethylpiperidine oxide, 0.082mmol of tetrabutylammonium chloride, 0.41mmol of sodium bicarbonate and 0.16mmol of chlorosuccinimide are sequentially added, the reaction solution is stirred for 2 hours, 10mL of saturated sodium bicarbonate solution is used for quenching reaction, dichloromethane extraction is carried out, an organic layer is washed by saturated saline and dried by anhydrous sodium sulfate, reduced pressure concentration is carried out, and a product is separated and purified by a silica gel column chromatography to obtain a light yellow oily substance, namely the gem-dimethyldiketone compound 16; the yield of step 13 was 95%;
Step 14:
Cooling a solution of 0.066mmol of gem-dimethyl diketone compound 16 in 5mL of dichloromethane to 0 ℃, sequentially and slowly adding 0.66mmol of triethylamine and 0.264mmol of trimethyl silicone triflate, stirring the reaction solution at 0 ℃ for 30 minutes, quenching reaction by 10mL of saturated sodium bicarbonate, extracting dichloromethane, washing an organic layer with saturated saline water, drying by anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a gem-dimethyl silyl ether compound 17;
step 15:
Dissolving 0.066mmol of the gem-dimethyl silyl ether compound 17 shown in the above formula in 5mL of acetonitrile, adding 0.132mmol of palladium trifluoroacetate, stirring the reaction solution for 3 hours, filtering with silica gel, concentrating under reduced pressure, and separating and purifying the product by using a silica gel column chromatography to obtain white powdery solid, namely the gem-dimethyl ketene compound 18; the total yield of steps 14 and 15 was 95%;
Step 16:
Cooling 0.042mmol of a 4mL toluene solution of the gem-dimethyl ketene compound 18 shown in the formula to 0 ℃, slowly and dropwise adding 53 mu L of a 1.6M diethyl ether solution of methyl lithium, stirring for 30min, quenching reaction by 10mL saturated ammonium chloride solution, extracting by diethyl ether, washing an organic layer with saturated saline water and drying by anhydrous sodium sulfate, concentrating under reduced pressure, and separating and purifying a product by a silica gel column chromatography to obtain a light yellow oily substance, namely the gem-dimethyl allyl alcohol compound 19;
step 17:
To a solution of 0.042mmol of the above-mentioned geminal dimethylallyl alcohol compound 19 in 3mL of methylene chloride, 18mg of silica gel, 0.084mmol of sodium acetate and 0.084mmol of pyridinium chlorochromate were sequentially added, the mixture was stirred for 30 minutes, then 84. Mu.L of 2M aqueous hydrochloric acid solution was added, stirred for 30 minutes, 2mL of saturated sodium bicarbonate was used for quenching reaction, extracted with methylene chloride, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the purified product was separated by silica gel column chromatography to obtain a white powdery solid, which was pepluanolA; the overall yield of steps 16 and 17 was 59%.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Diastereoselective Total Synthesis of the Euphorbia Diterpenoid Pepluanol A: A Reductive Annulation Approach;Jun Xuan等;《Angew. Chem. Int. Ed.》;第56卷;8898-8901 *
Ten-Step Asymmetric Total Synthesis of (+)-Pepluanol A;Po Yuan等;《J. Am. Chem. Soc.》;第143卷;11934−11938 *
天然产物Steenkrotin B和Pepluanol A的全合成研究;宣军;《中国博士学位论文全文数据库 工程科技Ⅰ辑》(第07期);第B014-36页 *
宣军.天然产物Steenkrotin B和Pepluanol A的全合成研究.《中国博士学位论文全文数据库 工程科技Ⅰ辑》.2017,(第07期),第B014-36页. *

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