CN114560760A - Method for synthesizing diterpene Pepluanol A in Euphorbiaceae - Google Patents

Method for synthesizing diterpene Pepluanol A in Euphorbiaceae Download PDF

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CN114560760A
CN114560760A CN202210105174.9A CN202210105174A CN114560760A CN 114560760 A CN114560760 A CN 114560760A CN 202210105174 A CN202210105174 A CN 202210105174A CN 114560760 A CN114560760 A CN 114560760A
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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 diterpene Pepluanol A in Euphorbiaceae, which belongs to the field of organic synthesis. The synthetic method is simple and convenient to operate, the product is obtained by 17 steps, 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, cheap and easily obtained raw materials and strong compatibility of each important functional group, is convenient to synthesize various derivatives with the same 5/6/7 fused ring skeleton and euphorbiaceae diterpene structure, and lays a foundation for the research of structure-activity relationship of the compounds.

Description

Method for synthesizing diterpene Pepluanol A in Euphorbiaceae
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a synthesis method of diterpene Pepluanol A in Euphorbiaceae.
Background
Natural products play an important role in the development of the human society as a valuable wealth of nature. Drug development based on natural products has been the central focus of drug development. Statistics show that more than half of clinical new drugs approved by FDA over the years are derived from natural products or derivatives thereof. China has abundant natural product resources and a long-standing traditional Chinese medicine theory, and the combination of the two has great significance for researching and developing new drugs with independent intellectual property rights.
Medicinal plants from the euphorbiaceae family are used in traditional chinese medicine for treating diseases such as asthma and psoriasis, and among them, natural products of the euphorbiaceae family are often used for playing important active roles. Due to the diversity of the structure and biological activity of euphorbiaceae natural products, it is often the main source of natural drug discovery. However, the amount of natural products obtained by separation is usually very small, and large-scale preparation cannot be achieved, so that the total synthesis of natural products becomes an important intermediate link for linking active ingredient discovery and pharmaceutical chemistry research.
Diterpenoid compounds are natural products with complex and various structures and important biological activity, new strategies and new methods are designed and developed to realize simple, convenient and efficient synthesis, and the diterpenoid compounds have important scientific and practical significance for promoting new organic synthesis methods, new theoretical development and new drug discovery, and the synthesis methods of part of diterpenoid compounds are reported in the prior art, such as: chinese patent publication No. CN108503652A discloses a chemical total synthesis method of crotonaldehyde diterpene Prostratin, which comprises using easily prepared 5- (hydroxymethyl) -2-cyclopentene-1-ol as raw material, performing key reactions such as light oxidation dearomatization, intramolecular induction addition reaction, olefin metathesis reaction, and finally performing functional group conversion to obtain the target product.
Chinese patent publication No. CN105152992A discloses a method for synthesizing cyclopiane tetracyclic diterpene natural products (conidiosene b, conidiogenone and conidiogenol), which comprises synthesizing an intermediate having a conjugated ketene and a cyclobutanol structure from known conjugated esters, performing rearrangement reaction under the action of acid to construct a tricyclic framework structure of tetracyclic diterpene, performing structural modification and cyclization reaction under the action of acid to construct a tetracyclic framework structure of tetracyclic diterpene, and then synthesizing the cyclopiane tetracyclic diterpene natural product through multi-step chemical transformation with the tetracyclic diterpene framework as a key intermediate.
The euphorbiaceae diterpene Pepluanol A is originally separated from acetone extract of Euphorbia peplus, has a [5,4,7,3] tetracyclic framework, contains 7 chiral centers in total, 6 continuous chiral centers and a quaternary carbon, forms a highly compact fused ring framework, is difficult to synthesize, and shows the biological activity of blocking Kv1.3 potassium ion channels, and can potentially treat T cell mediated immune diseases such as type I diabetes, asthma and the like.
Disclosure of Invention
The invention provides a method for synthesizing Euphorbiaceae diterpene Pepluanol A, which starts from racemic raw materials, has controllable reaction sites in each step and higher total yield which reaches 2.5 percent. Realizes 17-step total synthesis of diterpene Pepluanol A in Euphorbiaceae, and lays a foundation for further research on structure-activity relationship of diterpene compounds in Euphorbiaceae.
The technical scheme is as follows:
a method for synthesizing the diterpene Pepluanol A in Euphorbiaceae comprises the following steps:
step 1: dissolving the ketene compound 2 in an organic solvent, adding azidotrimethylsilane, an iodo reagent and organic base, and reacting to obtain an alkenyl iodo compound 3;
and 2, step: dissolving alkenyl iodine compound 3 in an organic solvent, adding organic phosphine, a metal palladium catalyst and an organic zinc reagent, and reacting to obtain an ketene compound 4;
and 3, step 3: mixing the ketene compound 4 and the conjugated diene ether compound, reacting to obtain a mixture, dissolving the mixture by using an organic solvent, adding hydrochloric acid, and further reacting to obtain a diketone compound 6;
and 4, step 4: dissolving diketone compounds 6 in an organic solvent, adding a trifluoromethanesulfonylation reagent and strong base, and reacting to obtain trifluoromethanesulfonate compounds 7;
and 5: dissolving the trifluoromethanesulfonate 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 an inorganic base, and reacting to obtain a hemiketal compound 9;
And 7: dissolving the hemiketal compound 9 in an organic solvent, adding water, inorganic base and a peroxidation reagent, and reacting to obtain an epoxy compound 10;
and step 8: dissolving an epoxy compound 10 in an organic solvent, adding organic phosphine and an azodicarboxylic ester compound, and reacting to obtain a triene compound 11;
and step 9: dissolving a triene compound 11 in an organic solvent, adding water, organic base, a catalytic amount of oxidant and an equivalent amount of oxidant, and reacting to obtain an aldehyde compound 12;
step 10: mixing an organic metal titanium reagent and a reducing metal, adding an organic base 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 cyclopropane compound 14, methyl iodide, methyl metal reagent and organic base to obtain geminal dimethyl cyclopropane compound 15;
step 13: dissolving the geminal dimethylcyclopropane compound 15 in a mixed solvent, and then adding a nitrogen oxide, a phase transfer catalyst, an inorganic base and an oxidant to react to obtain a geminal dimethyldione 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 silicon ether compound 17;
step 15: dissolving the dimethyl silicon ether compound 17 in an organic solvent, adding a metal palladium catalyst, and reacting to obtain a 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;
and step 17: dissolving the gem-dimethyl allyl alcohol compound 19 in an organic solvent, adding silica gel, inorganic salt and an oxidant, stirring, adding hydrochloric acid, and then continuously stirring to obtain the euphorbiaceae diterpene Pepluanol A with the structure shown in the formula I;
Figure BDA0003493713150000041
preferably, in step 1, the iodination reagent is elemental iodine or N-iodosuccinimide; the organic base is pyridine, triethylamine, 4-dimethylamino pyridine or 1, 4-diazabicyclo [2.2.2] octane; the mol ratio of the ketene compound 2, the organic base, the iodinating reagent and the azidotrimethylsilane is 1: 4-5: 1-1.5: 1 to 1.5; the ratio of the ketene compound 2 to the organic solvent is 1 mmol: 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 acetone palladium), palladium acetate, tetrakis (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 1 mmol: 3-5 mL; the mol ratio of the alkenyl iodine compound 3 to the organic zinc reagent to the organic phosphine to the metal palladium catalyst is 1: 1.0-1.5: 0.1-0.5: 0.05 to 0.1.
Preferably, in step 3, the conjugated diene ether compound is Rawal diene; the mol 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 trifluoromethanesulfonylation reagent is N-phenyl bis (trifluoromethanesulfonyl) imide, 2- [ N, N-bis (trifluoromethanesulfonyl) amino ] -5-chloropyridine or trifluoromethanesulfonic anhydride; the proportion of the diketone compound 6 to the organic solvent is 1 mmol: 5-10 mL; the molar ratio of the diketone compound 6 to the strong base to the trifluoromethanesulfonylation reagent is 1: 1.1-1.5: 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, trimethyl aluminum, methyl magnesium iodide or methyl lithium; the ratio of the triflate compound 7 to the organic solvent is 1 mmol: 5-10 mL; the mol ratio of the trifluoromethanesulfonate compound 7 to the metallic copper catalyst to the methyl metal reagent is 1: 0.05-0.1: 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 mol ratio of the conjugated diene compound 8 to the inorganic base is 1: 3; the ratio of the conjugated diene compound 8 to the organic solvent is 1 mmol: 5-10 mL.
Preferably, in step 7, the inorganic base is sodium bicarbonate, potassium bicarbonate or sodium acetate; the peroxidation reagent is potassium peroxymonosulfonate, hydrogen peroxide, m-chloroperoxybenzoic acid or acetone peroxide; the proportion of the hemiketal compound 9 to the organic solvent is 1 mmol: 5-10 mL; the mol ratio of the hemiketal compound 9 to the inorganic base to the peroxidation reagent 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 1 mmol: 10-15 mL; the molar ratio of the epoxy compound 10 to the organic phosphine to the azodicarboxylic acid compound is 1: 2-4: 2 to 4.
Preferably, in step 9, the organic base is 2, 6-lutidine, pyridine or tetramethylethylenediamine; the catalytic amount of the oxidizing agent is osmium tetroxide or potassium osmate; the equivalent oxidant is periodic acid or sodium periodate; the ratio of the triene compound 11 to the organic solvent is 1 mmol: 12-17 mL; the molar ratio of the triene compound 11, the organic base, the catalytic amount of the oxidizing agent and the equivalent oxidizing agent is 1: 1-3: 0.05-0.15: 3 to 5.
Preferably, in step 10, the organometallic titanium reagent is titanocene dichloride; the reducing metal is zinc powder or manganese powder; the organic base hydrochloride is 2,4, 6-trimethylpyridine hydrochloride; the mol ratio of the aldehyde compound 12, the reducing metal, the organic metal titanium reagent and the organic base hydrochloride is 1: 1-5: 1: 1.
preferably, in step 11, the phase transfer catalyst is benzyltriethylammonium chloride, tetrabutylammonium bromide or tetrabutylammonium iodide; the inorganic strong base is potassium tert-butoxide, sodium hydroxide or potassium hydroxide; the proportion of the diol compound 13 to the organic halogenated solvent is 1 mmol: 20-50 mL; the mass ratio of the diol compound 13 to the phase transfer catalyst to the inorganic strong base is 1: 0.05-0.1: 50.
Preferably, in step 12, the methyl metal reagent is methyl lithium or methyl copper lithium; the organic base is hexamethyl phosphoric triamide or N, N-dimethyl propylene urea; the mol 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 benzyltriethylammonium chloride, tetrabutylammonium bromide or tetrabutylammonium iodide; the oxidant is chlorosuccinimide, sodium hypochlorite or iodobenzene acetate; the nitrogen oxide is tetramethylpiperidine nitrogen oxide or 2-azaadamantane-N-oxyl radical; the proportion of the geminal dimethylcyclopropane compound 15 to the mixed solvent is 1 mmol: 100-150 mL; the mass ratio of the geminal dimethylcyclopropane compound 15, the inorganic base, the phase transfer catalyst, the oxidant and the nitrogen oxide is 1: 4-6: 1: 1-3: 0.05 to 0.2.
Preferably, in step 14, the organic base is triethylamine, 2, 6-lutidine or pyridine; the silicon-based reagent is trimethylsilyl trifluoromethanesulfonate, triethylsilyl trifluoromethanesulfonate or tert-butyldimethylsilyl trifluoromethanesulfonate; the proportion of the gem-dimethyl diketone compound 16 to the organic solvent is 1 mmol: 50-100 mL; the molar ratio of the gem-dimethyl diketone compound 16 to the organic base to 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 dimethyl silicon ether compound 17 to the organic solvent is 1 mmol: 50-100 mL; the molar ratio of the 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, trimethyl aluminum or methyl lithium; the proportion of the gem-dimethyl ketene compound 18 to the organic solvent is 1 mmol: 50-100 mL; the molar ratio of the gem-dimethyl ketene 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-dimethyl allyl alcohol compound 19 to the organic solvent is 1 mmol: 50-100 mL; the mass ratio of the gem-dimethyl allyl alcohol compound 19 to the silica gel to the inorganic salt to the oxidant is 1: 1-1.5: 0.5-1: 0.5 to 1.
Further preferably, in step 10, the reducing metal is manganese powder; in step 12, the organic base is N, N-dimethylpropyleneurea; the manganese powder and the N, N-dimethyl propylene urea are selected, so that the yield can be ensured, and the operation safety can be improved; in the step 15, the metal palladium catalyst is palladium trifluoroacetate, the selection of the conditions can enable the yield to reach 95%, and the strong electron-withdrawing property of the trifluoro acetate enables the trifluoroacetate anions to have stronger alkalinity, so that the beta hydrogen elimination of the palladium is more efficient. Chemoselectivity and stereoselectivity are always key factors for the development of fine organic synthesis, and the site selectivity of reaction is closely and inseparably connected with yield, the properties of a catalyst, a ligand, a substrate and the like.
Compared with the prior art, the invention has the beneficial effects that:
(1) the synthetic route adopted by the invention is to use easily prepared cycloheptenone derivatives as starting materials, construct a key tricyclic framework through key steps of Negishi coupling reaction, Diels-Alder reaction, titanium free radical catalyzed cascade cyclization reaction and the like, and finally obtain the target product euphorbiaceae diterpene Pepluanol A through later-stage functional group conversion.
(2) The synthetic method is simple and convenient to operate, the product is obtained by 17 steps, the condition is mild, and the total yield reaches 2.5%. The synthesized product was consistent with the NMR spectrum data of the natural product.
(3) The synthetic route of the invention has novel design thought, cheap and easily obtained raw materials and strong compatibility of each important functional group, is convenient to synthesize various derivatives with the same 5/6/7 fused ring skeleton and euphorbiaceae diterpene structure, and lays a foundation for the research of structure-activity relationship of the compounds.
Drawings
FIG. 1 is a scheme showing the synthesis of the diterpene Pepluanol A compound of the Euphorbiaceae family in the present invention.
FIG. 2 is a hydrogen spectrum of the diterpene Pepluanol A compound of the Euphorbiaceae family according to the present invention.
FIG. 3 is a carbon spectrum of a compound of the present invention, Euphorbiaceae diterpene Pepluanol A.
Detailed Description
The invention is further elucidated with reference to the figures and the examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
Example 1
The synthetic scheme for the Pepluanol a compound is shown in figure 1.
Step 1:
Figure BDA0003493713150000081
azidotrimethylsilane (11.9mL,0.09mol) is added to a dichloromethane (200mL) solution of ketene compound 2 (20g,0.082mol) at the temperature of 0 ℃, after stirring for 2 hours, elementary iodine (22.86g,0.09mol) and pyridine (26.5mL,0.33mol) are sequentially added, the mixed solution is slowly heated to room temperature and stirred for 24 hours, 50mL of saturated ammonium chloride solution is used for quenching reaction, the mixed solution is extracted by dichloromethane, washed by saturated saline and dried by anhydrous sodium sulfate, the reaction product is concentrated under reduced pressure, and the product is separated and purified by silica gel column chromatography to obtain light yellow oily substance, namely, the alkenyl iodine compound 3(26.7g, 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:
Figure BDA0003493713150000082
to a solution of anhydrous zinc chloride (8.08g,59.4mmol) in tetrahydrofuran (100mL) at-78 deg.C was slowly added 3-butenyl magnesium bromide (0.5M in tetrahydrofuran, 118.8mL,59.4mmol) and the mixture was slowly raised to 0 deg.C to afford 3-butenyl zinc bromide reagent for use.
To a solution of alkenyl iodine compound 3(20g,54.0mmol) in N, N-dimethylformamide (200mL), tris (2-furyl) phosphine (3.1g,5.4mmol) and palladium bis (dibenzylideneacetone) (626.4mg,2.7mmol) were added in this order, the mixture was stirred for 10min, and then the above 3-butenyl zinc bromide reagent (220mL,0.054mol) was slowly added dropwise, after stirring for 1 hour, 50mL saturated ammonium chloride was quenched, extracted with diethyl ether, washed with saturated brine and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the product was isolated and purified by silica gel column chromatography to give a pale yellow oil, namely, an ketene compound 4(11.9g, 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。
and step 3:
Figure BDA0003493713150000091
rawal diene 5(13.3mL,51mmol) is added to ketene compound 4(10g,34mmol) shown in the formula, the reaction solution is stirred at 40 ℃ for 24 hours, the obtained mixture is dissolved in tetrahydrofuran (200mL), the temperature is cooled to-30 ℃, hydrochloric acid (2M aqueous solution, 68mL,136mol) is slowly added dropwise, the mixed solution is slowly heated to room temperature and stirred for 24 hours, 100mL saturated sodium bicarbonate is used for quenching reaction, ethyl acetate is used for extraction, an organic layer is washed by saturated saline solution and dried by anhydrous sodium sulfate, reduced pressure concentration is carried out, and a white powdery solid, namely, diketone compound 6(10.3g, 83%) is obtained after separation and purification of a product by silica gel column chromatography.
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。
and 4, step 4:
Figure BDA0003493713150000101
n-phenylbis (trifluoromethanesulfonyl) imide (13.33g,37.3mmol) is added to a tetrahydrofuran (200mL) solution of diketone compound 6(11.94g, 33.9mmol) shown in the formula, the mixed solution is cooled to-78 ℃, bis (trimethylsilyl) amino potassium (1M tetrahydrofuran solution, 37.3mL, 37.3mmol) is slowly added dropwise, the mixture is slowly heated to room temperature and stirred for 1 hour, 50mL saturated ammonium chloride is used for quenching reaction, ethyl acetate is used for extraction, an organic layer is washed with saturated common salt solution and dried with anhydrous sodium sulfate, reduced pressure concentration is carried out, and a product is separated and purified by silica gel column chromatography to obtain a light yellow oily substance, namely the trifluoromethanesulfonate compound 7(15.6g,29.5 mmol).
And 5:
Figure BDA0003493713150000111
to a tetrahydrofuran (200mL) solution of the trifluoromethanesulfonate compound 7(15.6g,29.5mmol) shown in the formula, cuprous iodide (280mg,1.48mmol) was added, the mixture was cooled to 0 ℃, methylmagnesium bromide (3M diethyl ether solution, 19.7mL,59mmol) was slowly added dropwise, the reaction mixture was stirred for 3 hours, 50mL of saturated ammonium chloride was quenched, the ether was extracted, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the product was separated and purified by silica gel column chromatography to obtain a pale yellow oil, i.e., the conjugated diene compound 8(8.9g, total yield of step 4 and step 5 was 72%).
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:
Figure BDA0003493713150000121
adding sodium methoxide (4.5g,82.5mmol) into a methanol (200mL) solution of the conjugated diene compound 8(10g,27.5mmol) shown in the formula in batches, refluxing and stirring the reaction solution for 8 hours, quenching the reaction by 50mL of saturated ammonium chloride, extracting with diethyl ether, washing an organic layer with saturated saline solution, drying the organic layer with anhydrous sodium sulfate, concentrating under reduced pressure, and separating and purifying the product by silica gel column chromatography to obtain a light yellow oily substance, namely the hemiketal compound 9(5.9g,22.8 mmol).
And 7:
Figure BDA0003493713150000122
dissolving hemiketal compound 9(5.9g,22.8mmol) shown in the formula in acetone (120mL), sequentially adding water (30mL), sodium bicarbonate (9.6g,114mmol) and potassium peroxymonosulfonate (21g,68.4mmol), stirring the reaction solution for 1 hour, quenching the reaction by 100mL saturated sodium bicarbonate, extracting with diethyl ether, washing the organic layer with saturated saline water and drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating and purifying the product by silica gel column chromatography to obtain light yellow oily substance, namely epoxy compound 10(4.4g, the total yield of step 6 and step 7 is 58%).
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。
and step 8:
Figure BDA0003493713150000131
triphenylphosphine (3.8g,14.4mmol) and diethyl azodicarboxylate (2.2mL,14.4mmol) were sequentially added to a tetrahydrofuran (50mL) solution of epoxy compound 10(1g,3.6mmol) shown in the formula, the reaction mixture was stirred at 60 ℃ for 1 hour, 25mL saturated sodium bicarbonate was quenched, ether was extracted, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the product was separated and purified by silica gel column chromatography to give a pale yellow oil, that is, triene compound 11(622mg, 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。
and step 9:
Figure BDA0003493713150000141
to a solution of triene compound 11(500mg,1.94mmol) represented by the formula in 1, 4-dioxane (30mL) were added water (10mL), 2, 6-lutidine (450. mu.L, 3.88mmol), osmium tetroxide (2% by mass aqueous solution, 2.54mL,0.2mmol) and sodium periodate (1.67g,7.76mmol) in this order, the mixture was stirred for 3 hours, 25mL of saturated sodium thiosulfate was quenched, dichloromethane was extracted, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the product was separated and purified by silica gel column chromatography to give a pale yellow oily substance, that is, aldehyde compound 12(353mg, 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:
Figure BDA0003493713150000151
dissolving titanocene dichloride (191mg,0.77mmol) and manganese powder (170mg,3.08mmol) in tetrahydrofuran (25mL), vigorously stirring for 10 minutes to turn green, adding 2,4, 6-trimethylpyridine hydrochloride (151mg,0.77mmol), stirring for 5 minutes, slowly dropping a tetrahydrofuran (15mL) solution of aldehyde compound 12(200mg,0.77mmol) shown in the formula in 1 hour, stirring the reaction solution for 2 hours, filtering with diatomite, concentrating the filtrate under reduced pressure, and separating and purifying the product by silica gel column chromatography to obtain white powdery solid, namely diol compound 13(199mg, 99%, diastereoisomer ratio of 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:
Figure BDA0003493713150000161
to a bromoform (5mL) solution of a diol compound 13(50mg,0.19mmol, diastereomer ratio 1:1) represented by the formula, benzyltriethylammonium chloride (4.3mg) and sodium hydroxide (50% by mass of an aqueous solution, 5mL) were sequentially added, the reaction solution was stirred at 50 ℃ for 2 hours, the reaction was quenched with 10mL of a saturated ammonium chloride solution at 0 ℃, dichloromethane was extracted, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the product was separated and purified by silica gel column chromatography to obtain a pale yellow oily substance, i.e., a cyclopropane compound 14.
Step 12:
Figure BDA0003493713150000162
cooling the freshly dried cuprous thiocyanate (413mg,3.4mmol) in diethyl ether (30mL) to-78 deg.C, slowly adding dropwise methyllithium (1.6M diethyl ether solution, 4.3mL,6.8mmol), slowly raising the reaction solution to-20 deg.C, slowly adding dropwise a solution of cyclopropane compound 14(71mg,0.17mmol) and N, N-dimethylpropylurea (217. mu.L, 1.7mmol) in diethyl ether (15mL) to the reaction solution, stirring for 1 hour, adding iodomethane (414. mu.L, 6.8mmol), stirring the reaction solution for 30min, quenching with 20mL saturated ammonium chloride, extracting diethyl ether, washing the organic layer with saturated saline and drying over anhydrous sodium sulfate, concentrating under reduced pressure, separating and purifying the product with silica gel column chromatography to obtain a light yellow oil, i.e. geminal dimethylcyclopropane compound 15(25 mg; total yield of step 11 and step 12 is 44%, diastereomer ratio 1: 1).
Diastereomer 1 bulk 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 spectral 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 spectral data:
HRMS(ESI):calcd for C19H29O3 +[M+H]+305.2111,found 305.2109。
step 13:
Figure BDA0003493713150000171
to a mixed solution of 15(25mg,0.082mmol) of gem-dimethyl cyclopropane compound shown in the formula and dichloromethane (5mL) and water (5mL) are added sequentially tetramethyl piperidine oxide (2mg,0.008mmol), tetrabutyl ammonium chloride (23mg,0.082mmol), sodium bicarbonate (35mg,0.41mmol) and chlorosuccinimide (22mg,0.16mmol), the reaction solution is stirred for 2 hours, 10mL saturated sodium bicarbonate solution is quenched, dichloromethane is extracted, an organic layer is washed by saturated sodium chloride solution and dried by anhydrous sodium sulfate, reduced pressure concentration is carried out, and a product is separated and purified by silica gel column chromatography to obtain a light yellow oily substance, namely the gem-dimethyl diketone compound 16(23.5mg, 95%).
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:
Figure BDA0003493713150000181
cooling the mixture of the gem-dimethyl diketone compound 16(20mg,0.066mmol) in dichloromethane (5mL) to 0 ℃, adding triethylamine (91 muL, 0.66mmol) and trimethylsilyl trifluoromethanesulfonate (48 muL, 0.264mmol) slowly in turn, stirring the reaction solution at 0 ℃ for 30 minutes, quenching the reaction solution with 10mL saturated sodium bicarbonate, extracting the dichloromethane, washing the organic layer with saturated saline water and drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the gem-dimethyl silicon ether compound 17(25 mg).
Step 15:
Figure BDA0003493713150000191
dissolving the gem-dimethyl-silicon ether compound 17(25mg,0.066mmol) shown in the formula in acetonitrile (5mL), adding palladium trifluoroacetate (43mg,0.132mmol), stirring the reaction liquid for 3 hours, filtering the silica gel, concentrating under reduced pressure, and separating and purifying the product by silica gel column chromatography to obtain a white powdery solid, namely the gem-dimethyl-ketene compound 18(23mg, the total yield of the step 14 and the step 15 is 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:
Figure BDA0003493713150000192
cooling the germul dimethyl ketene compound 18(15mg,0.042mmol) in toluene (4mL) to 0 ℃, slowly adding methyl lithium (1.6M diethyl ether solution, 53 mu L,0.084mmol) dropwise, stirring for 30min, quenching the reaction in 10mL saturated ammonium chloride solution, extracting with diethyl ether, washing the organic layer with saturated saline solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating and purifying the product by silica gel column chromatography to obtain a light yellow oily substance, namely the germul dimethyl allyl alcohol compound 19(13 mg).
And step 17:
Figure BDA0003493713150000201
to a solution of the gem-dimethylallyl alcohol compound 19(13mg,0.042mmol) shown in the formula shown in the specification in dichloromethane (3mL) were added silica gel (18mg), sodium acetate (7mg,0.084mmol) and pyridinium chlorochromate (9mg,0.084mmol) in this order, the mixture was stirred for 30 minutes, then hydrochloric acid (2M aqueous solution, 84. mu.L, 0.168mmol) was added, stirred for 30 minutes, 2mL saturated sodium bicarbonate was used to quench the reaction, dichloromethane was used for extraction, the organic layer was washed with saturated sodium chloride and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the product was isolated and purified by silica gel column chromatography to give a white powdery solid, namely pepluanol A (7.7 mg; total yield of step 16 and step 17 was 59%).
The nuclear magnetic resonance hydrogen spectrum and the nuclear magnetic resonance carbon spectrum of the product pepluanol A are respectively shown in fig. 2 and fig. 3, and the NMR spectrum data of the product synthesized by the method of the invention is consistent with that of a 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。
the embodiments described above are intended to illustrate the technical solutions of the present invention in detail, and it should be understood that the above-mentioned embodiments are only specific embodiments of the present invention, and are not intended to limit the present invention, and any modification, supplement or similar substitution made within the scope of the principles of the present invention should be included in the protection scope of the present invention.

Claims (10)

1. A method for synthesizing the diterpene Pepluanol A in the Euphorbiaceae family is characterized by comprising the following steps:
step 1: dissolving the ketene compound 2 in an organic solvent, adding azidotrimethylsilane, an iodinating reagent and organic base, and reacting to obtain an alkenyl iodine compound 3;
and 2, step: dissolving alkenyl iodine compound 3 in an organic solvent, adding organic phosphine, a metal palladium catalyst and an organic zinc reagent, and reacting to obtain an ketene compound 4;
and 3, step 3: mixing the ketene compound 4 and the conjugated diene ether compound, reacting to obtain a mixture, dissolving the mixture by using an organic solvent, adding hydrochloric acid, and further reacting to obtain a diketone compound 6;
and 4, step 4: dissolving diketone compounds 6 in an organic solvent, adding a trifluoromethanesulfonylation reagent and strong base, and reacting to obtain trifluoromethanesulfonate compounds 7;
and 5: dissolving the trifluoromethanesulfonate 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 an inorganic base, and reacting to obtain a hemiketal compound 9;
and 7: dissolving the hemiketal compound 9 in an organic solvent, adding water, inorganic base and a peroxidation reagent, and reacting to obtain an epoxy compound 10;
And step 8: dissolving an epoxy compound 10 in an organic solvent, adding organic phosphine and an azodicarboxylic ester compound, and reacting to obtain a triene compound 11;
and step 9: dissolving a triene compound 11 in an organic solvent, adding water, organic base, a catalytic amount of oxidant and an equivalent amount of oxidant, and reacting to obtain an aldehyde compound 12;
step 10: mixing an organic metal titanium reagent and a reducing metal, adding an organic base 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 cyclopropane compound 14, methyl iodide, methyl metal reagent and organic base to obtain geminal dimethyl cyclopropane compound 15;
step 13: dissolving the geminal dimethylcyclopropane compound 15 in a mixed solvent, and then adding a nitrogen oxide, a phase transfer catalyst, an inorganic base and an oxidant to react to obtain a geminal dimethyldione 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 silicon ether compound 17;
Step 15: dissolving the dimethyl silicon ether compound 17 in an organic solvent, adding a metal palladium catalyst, and reacting to obtain a 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;
and step 17: dissolving the gem-dimethyl allyl alcohol compound 19 in an organic solvent, adding silica gel, inorganic salt and an oxidant, stirring, adding hydrochloric acid, and then continuously stirring to obtain the euphorbiaceae diterpene Pepluanol A with the structure shown in the formula I;
Figure FDA0003493713140000021
2. the method of claim 1, wherein the diterpene Pepluanol A of Euphorbiaceae is synthesized,
in the step 1, the iodination reagent is elemental iodine or N-iodosuccinimide; the organic base is pyridine, triethylamine, 4-dimethylamino pyridine or 1, 4-diazabicyclo [2.2.2] octane;
in the step 2, the organic phosphine is tri (2-furyl) phosphine, triphenylphosphine or tributylphosphine; the metal palladium catalyst is bis (dibenzylidene acetone palladium), palladium acetate, tetrakis (triphenylphosphine) palladium, palladium chloride or bis (acetonitrile) palladium dichloride; the organic zinc reagent is 3-butenyl zinc bromide;
In the step 3, the conjugated diene ether compound is Rawal diene;
in the step 4, the trifluoromethanesulfonylation reagent is N-phenyl bis (trifluoromethanesulfonyl) imide, 2- [ N, N-bis (trifluoromethanesulfonyl) amino ] -5-chloropyridine or trifluoromethanesulfonic anhydride; the strong base is potassium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide or lithium diisopropylamide;
in the step 5, the metallic copper catalyst is cuprous iodide, cuprous bromide or cuprous dimethyl sulfide bromide; the methyl metal reagent is methyl magnesium bromide, trimethyl aluminum, methyl magnesium iodide or methyl lithium.
3. The method of claim 1, wherein the diterpene Pepluanol A of Euphorbiaceae is synthesized,
in the step 6, the inorganic base is sodium ethoxide, potassium carbonate, sodium methoxide, potassium tert-butoxide or sodium tert-butoxide;
in step 7, the inorganic base is sodium bicarbonate, potassium bicarbonate or sodium acetate; the peroxidation reagent is potassium peroxymonosulfonate, hydrogen peroxide, m-chloroperoxybenzoic acid or acetone peroxide.
4. The method of claim 1, wherein the diterpene Pepluanol A of Euphorbiaceae is synthesized,
In the step 8, the organic phosphine is tri (2-furyl) phosphine, triphenylphosphine or tributylphosphine; the azodicarboxylic acid ester compound is diethyl azodicarboxylate or diisopropyl azodicarboxylate.
5. The method of claim 1, wherein the diterpene Pepluanol A of Euphorbiaceae is synthesized,
in the step 9, the organic base is 2, 6-dimethylpyridine, pyridine or tetramethylethylenediamine; the catalytic amount of the oxidizing agent is osmium tetroxide or potassium osmate, and the equivalent oxidizing agent is periodic acid or sodium periodate;
in step 10, the organic metal titanium reagent is titanocene dichloride; the reducing metal is zinc powder or manganese powder; the organic base hydrochloride is 2,4, 6-trimethylpyridine hydrochloride.
6. The method of claim 1, wherein the diterpene Pepluanol A of Euphorbiaceae is synthesized,
in step 11, the phase transfer catalyst is benzyltriethylammonium chloride, tetrabutylammonium bromide or tetrabutylammonium iodide; the inorganic strong base is potassium tert-butoxide, sodium hydroxide or potassium hydroxide;
in step 12, the methyl metal reagent is methyl lithium or methyl copper lithium; the organic base is hexamethylphosphoric triamide or N, N-dimethyl propylene urea.
7. The method for synthesizing the Euphorbiaceae diterpene Pepluanol A according to claim 1,
in step 13, the nitrogen oxide is tetramethylpiperidine nitrogen oxide or 2-azaadamantane-N-oxyl radical; the phase transfer catalyst is benzyltriethylammonium chloride, tetrabutylammonium bromide or tetrabutylammonium iodide; the inorganic base is sodium bicarbonate, potassium bicarbonate or sodium acetate; the oxidant is chlorosuccinimide, sodium hypochlorite or iodobenzene acetate.
8. The method of claim 1, wherein the diterpene Pepluanol A of Euphorbiaceae is synthesized,
in step 14, the organic base is triethylamine, 2, 6-lutidine or pyridine; the silicon-based reagent is trimethylsilyl trifluoromethanesulfonate, triethylsilyl trifluoromethanesulfonate or tert-butyldimethylsilyl trifluoromethanesulfonate;
in step 15, the metal palladium catalyst is palladium acetate or palladium trifluoroacetate.
9. The method of claim 1, wherein the diterpene Pepluanol A of Euphorbiaceae is synthesized,
in step 16, the methyl metal reagent is methyl magnesium bromide, methyl magnesium iodide, trimethyl aluminum or methyl lithium;
In step 17, the inorganic salt is sodium acetate or sodium bicarbonate; the oxidant is pyridinium chlorochromate or pyridinium dichromate.
10. The method according to claim 1, wherein in step 10, the reducing metal is manganese powder; in step 12, the organic base is N, N-dimethylpropyleneurea; in step 15, the metal palladium catalyst is palladium trifluoroacetate.
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