CN116947615A - Method for preparing marine terpene natural product based on deacidification coupling reaction of sclareolide carboxylate and benzoquinone compound - Google Patents
Method for preparing marine terpene natural product based on deacidification coupling reaction of sclareolide carboxylate and benzoquinone compound Download PDFInfo
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- sclareolide
- carboxylate
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- 229930014626 natural product Natural products 0.000 title claims abstract description 37
- 238000005859 coupling reaction Methods 0.000 title claims abstract description 36
- -1 sclareolide carboxylate Chemical class 0.000 title claims abstract description 36
- IMKJGXCIJJXALX-UHFFFAOYSA-N ent-Norambreinolide Natural products C1CC2C(C)(C)CCCC2(C)C2C1(C)OC(=O)C2 IMKJGXCIJJXALX-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 229940096995 sclareolide Drugs 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 title claims abstract description 22
- 150000003505 terpenes Chemical class 0.000 title claims abstract description 22
- 235000007586 terpenes Nutrition 0.000 title claims abstract description 19
- 239000012363 selectfluor Substances 0.000 claims abstract description 17
- 238000006114 decarboxylation reaction Methods 0.000 claims abstract description 13
- 150000004057 1,4-benzoquinones Chemical class 0.000 claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 239000003054 catalyst Substances 0.000 claims description 10
- 230000008878 coupling Effects 0.000 claims description 10
- 238000010168 coupling process Methods 0.000 claims description 10
- 239000007800 oxidant agent Substances 0.000 claims description 9
- 230000001590 oxidative effect Effects 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 claims description 7
- 239000004332 silver Substances 0.000 claims description 7
- 229910052709 silver Inorganic materials 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 6
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 6
- 125000000524 functional group Chemical group 0.000 claims description 4
- 230000004048 modification Effects 0.000 claims description 4
- 238000012986 modification Methods 0.000 claims description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 3
- 150000003863 ammonium salts Chemical class 0.000 claims description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical group [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 claims description 3
- 229910001958 silver carbonate Inorganic materials 0.000 claims description 3
- 229940096017 silver fluoride Drugs 0.000 claims description 3
- REYHXKZHIMGNSE-UHFFFAOYSA-M silver monofluoride Chemical compound [F-].[Ag+] REYHXKZHIMGNSE-UHFFFAOYSA-M 0.000 claims description 3
- 229910001961 silver nitrate Inorganic materials 0.000 claims description 3
- FJOLTQXXWSRAIX-UHFFFAOYSA-K silver phosphate Chemical compound [Ag+].[Ag+].[Ag+].[O-]P([O-])([O-])=O FJOLTQXXWSRAIX-UHFFFAOYSA-K 0.000 claims description 3
- 229940019931 silver phosphate Drugs 0.000 claims description 3
- 229910000161 silver phosphate Inorganic materials 0.000 claims description 3
- 159000000000 sodium salts Chemical class 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 13
- 230000015572 biosynthetic process Effects 0.000 abstract description 10
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 abstract description 8
- 238000009776 industrial production Methods 0.000 abstract description 4
- IMKJGXCIJJXALX-SHUKQUCYSA-N Norambreinolide Chemical compound CC([C@@H]1CC2)(C)CCC[C@]1(C)[C@@H]1[C@]2(C)OC(=O)C1 IMKJGXCIJJXALX-SHUKQUCYSA-N 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 229930004725 sesquiterpene Natural products 0.000 abstract description 2
- 238000011914 asymmetric synthesis Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 239000012043 crude product Substances 0.000 description 11
- 235000019439 ethyl acetate Nutrition 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 101710134784 Agnoprotein Proteins 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000008367 deionised water Substances 0.000 description 4
- 229910021641 deionized water Inorganic materials 0.000 description 4
- QLFLHSQZFRDPFM-YYWHXJBOSA-N (4as,6as,12bs)-4,4,6a,12b-tetramethyl-1,2,3,4a,5,6-hexahydrobenzo[a]xanthene-9,10-dione Chemical compound O=C1C(=O)C=C2C=C3[C@@]4(C)CCCC(C)(C)[C@@H]4CC[C@]3(C)OC2=C1 QLFLHSQZFRDPFM-YYWHXJBOSA-N 0.000 description 3
- QLFLHSQZFRDPFM-UHFFFAOYSA-N Puupehedione Natural products O=C1C(=O)C=C2C=C3C4(C)CCCC(C)(C)C4CCC3(C)OC2=C1 QLFLHSQZFRDPFM-UHFFFAOYSA-N 0.000 description 3
- 150000007942 carboxylates Chemical class 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 229940005561 1,4-benzoquinone Drugs 0.000 description 2
- ZJKWJHONFFKJHG-UHFFFAOYSA-N 2-Methoxy-1,4-benzoquinone Chemical compound COC1=CC(=O)C=CC1=O ZJKWJHONFFKJHG-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 235000019502 Orange oil Nutrition 0.000 description 2
- 235000004347 Perilla Nutrition 0.000 description 2
- 241000229722 Perilla <angiosperm> Species 0.000 description 2
- LOCMLXSTDCXZFJ-UHFFFAOYSA-N Puupehenone Natural products O=C1C(O)=CC2=CC3C4(C)CCCC(C)(C)C4CCC3(C)OC2=C1 LOCMLXSTDCXZFJ-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 2
- 238000009509 drug development Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000010502 orange oil Substances 0.000 description 2
- LOCMLXSTDCXZFJ-YHELAOLJSA-N puupehenone Chemical compound O=C1C(O)=CC2=C[C@@H]3[C@@]4(C)CCCC(C)(C)[C@@H]4CC[C@]3(C)OC2=C1 LOCMLXSTDCXZFJ-YHELAOLJSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 238000006050 Minisci radical substitution reaction Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241000221696 Sclerotinia sclerotiorum Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C46/00—Preparation of quinones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/26—All rings being cycloaliphatic the ring system containing ten carbon atoms
- C07C2602/28—Hydrogenated naphthalenes
Abstract
The patent relates to a method for preparing marine terpene natural products based on deacidification coupling reaction of sclareolide carboxylate or sclareolide carboxylic acid and benzoquinone compounds, belonging to the field of chemical synthesis. The invention takes sclareolide as raw material, realizes the Minisci decarboxylation coupling reaction of the dicyclo sesquiterpene carboxylate or sclareolide carboxylic acid and p-benzoquinone promoted by Selectfluor for the first time, shortens the synthesis steps of yahazunone from the previous 6-18 steps to 2 steps, and further realizes the asymmetric synthesis of a plurality of yahazunone natural products. The method has the characteristics of good step economy, simple and convenient operation, suitability for industrial production and the like.
Description
Technical Field
The invention relates to a method for preparing a marine terpene natural product based on deacidification coupling reaction of sclareolide carboxylate and benzoquinone compounds.
Background
Ocean skyThe biological activity detection of yahazunone, the natural product, shows that it has better antibacterial activity to sclerotinia sclerotiorum and EC thereof 50 The value was 9.47mg/L (Journal of Natural Product,2018,81 (9): 2010-2017). Based on the specificity of yahazunone structure, the yahazunone is used as a key intermediate, and can be involved in the synthesis of various marine terpene natural products through subsequent functional group conversion or structural modification. The natural product puupehedione has excellent angiogenesis inhibition effect and is an important lead compound (International Journal of Cancer,2004,110 (1): 31-38) for drug development. However, the pharmacological and pharmacodynamic research of the active marine terpene natural product is affected due to low content in the natural organism and difficult separation, and the chemical synthesis research can make up for the defect of insufficient raw material supply in the subsequent drug development.
Therefore, it is particularly necessary to develop a chemical synthesis method of yahazunone marine natural products. The synthesis report of the marine natural product yahazunone adopts a convergent coupling strategy so far, the synthesis route is as long as 18 steps, and the total yield is low. In 2012, baran tried direct coupling of various radical donors to benzoquinone compounds was unsuccessful (Journal of the American Chemical Society,2012,134 (20): 8432-8435). The invention successfully realizes the direct coupling of the sclareum carboxylate and the benzoquinone compound by searching and optimizing the conditions on the basis, and has the advantages of less reaction steps, simple and convenient operation, suitability for industrial production and the like.
Disclosure of Invention
The invention aims to provide a method for preparing a terpene natural product based on deacidification coupling reaction of sclareolide carboxylate and benzoquinone compounds, which has the advantages of few reaction steps and good product selectivity, and is suitable for industrial production.
A method for preparing marine terpene natural products based on deacidification coupling reaction of sclareolide carboxylate and benzoquinone compounds is characterized by comprising the following steps:
sclareolide carboxylate 1Or sclareolide carboxylic acid 1'>With benzoquinone compound 2Under the action of a Selectfluor oxidant and a silver catalyst, minisci decarboxylation coupling reaction is carried out to generate a coupling product 3->Or marine terpenoid natural product yahazunone->
The coupling product 3 is subjected to subsequent functional group conversion and structural modification to prepare the marine terpene natural product.
The perilla lactone carboxylate of the invention selects potassium salt, sodium salt and ammonium salt.
SelectFluor and SelectFluor II are selected as oxidizing agents.
The silver catalyst disclosed by the invention selects silver nitrate, silver phosphate, silver carbonate and silver fluoride as catalysts.
In the decarboxylation coupling reaction process, a dichloroethane/water mixed solvent is selected as a reaction solvent.
The reaction temperature in the decarboxylation coupling reaction process is 20-50 ℃ and the reaction time is 20-40 hours.
The invention has the following characteristics:
1. the Minisci decarboxylation coupling reaction of the dicyclo sesquiterpene carboxylate and the p-benzoquinone promoted by the Selectfluor is realized for the first time, the synthesis step of yahazunone is shortened from the previous 6-18 steps to 2 steps, and the yield is greatly improved;
2. the invention takes the Minisci reaction participated by the mild oxidant as the key reaction to realize the synthesis of a plurality of natural products, and has the advantages of fewer reaction steps, suitability for industrial production and the like.
Drawings
FIG. 1 is a structural diagram of yahazunone marine natural products.
FIG. 2 is a scheme showing a specific synthetic route for Minisci decarboxylation coupling in accordance with the present invention.
FIG. 3 is a specific synthetic route for the 8-epi-puupehenol natural product of the present invention.
FIG. 4 is a specific synthetic route for puupehenol natural products of the present invention.
Detailed Description
The invention is further described below with reference to the accompanying drawings:
a method for preparing marine terpene natural products based on deacidification coupling reaction of sclareolide carboxylate and benzoquinone compounds is characterized by comprising the following steps:
sclareolide carboxylate 1Or sclareolide carboxylic acid 1'>With benzoquinone compound 2Under the action of a Selectfluor oxidant and a silver catalyst, minisci decarboxylation coupling reaction is carried out to generate a coupling product 3->Or marine terpenoid natural product yahazunone->
Further, the coupling product 3 is subjected to subsequent functional group conversion and structural modification to prepare the marine terpene natural product.
Further, the perilla lactone carboxylate is selected from potassium salt, sodium salt and ammonium salt (M in the structural formula).
Further, the SelectFluor oxidant selects SelectFluor and SelectFluor II as the oxidant.
Further, the silver catalyst is selected from silver nitrate, silver phosphate, silver carbonate and silver fluoride as catalysts.
Further, the decarboxylation coupling reaction process selects dichloroethane/water mixed solvent as the reaction solvent.
Further, the reaction temperature in the decarboxylation coupling reaction process is 20-50 ℃ and the reaction time is 20-40 hours.
Example 1: synthesis of yahazunone, a natural product (see FIG. 2)
To a round bottom flask was added sclareolide (0.2 mmol,1.0 equiv.), 1, 4-benzoquinone (0.4 mmol,43 mg) and Selectfluor (142 mg,0.4mmol,2.0 equiv.) at room temperature. DCE ((1 mL) and deionized water (0.9 mL) were added and stirred at room temperature for about 1 minute under nitrogen protection with AgNO added 3 Aqueous solution (0.1 mL,0.4M in H) 2 O,0.04 mmol). Stirring was continued for 24 hours. Ethyl acetate (3 x 3 mL) and the crude product after spin-drying was purified by column chromatography to give the desired product (+) -yahazunone 41mg in 62% yield. 1 H NMR(400MHz,CDCl 3 ):δ6.72(d,J＝10.0Hz,1H),6.67(d,J＝10.2,2.8Hz,1H),6.59(s,1H),2.62(dd,J＝15.1,6.0Hz,1H),2.47(dd,J＝15.2,5.1Hz,1H),1.87(dt,J＝12.2,3.0Hz,1H),1.29-1.24(m,1H),1.20(s,3H),0.87(s,3H),0.86(s,3H),0.79(s,3H)； 13 C NMR(100MHz,CDCl 3 ):δ188.1,187.6,152.7,136.9,136.2,132.8,74.0,61.6,55.9,44.8,41.8,40.5,39.4,33.2(2C),24.6,23.8,21.5,20.3,18.4,15.1ppm.
Example 2: synthesis of yahazunone as natural product
Sclareic acid 1 'was added to a round bottom flask at room temperature'(0.2 mmol,1.0 equiv.), 1, 4-benzoquinone (0.4 mmol,43 mg), and Selectfluor (142 mg,0.4mmol,2.0 equiv.). DCE ((1 mL) and deionized water (0.9 mL) were added and stirred at room temperature for about 1 minute under nitrogen protection with AgNO added 3 Aqueous solution (0.1 mL,0.4M in H) 2 O,0.04 mmol). Stirring was continued for 24 hours. Acetic acid ethyl esterThe ester (3X 3 mL) was extracted and the crude product after spin-drying was purified by column chromatography to give 34mg of the desired product (+) -yahazunone in 51% yield.
Example 3: preparation of Compound 3a (3 a, see FIG. 3)
Carboxylate (0.2 mmol,1.0 equiv.), 2-methoxy-1, 4-benzoquinone (0.4 mmol,2.0 equiv.) and Selectfluor (142 mg,0.4mmol,2.0 equiv.) were added to the round bottom flask at room temperature. DCE (1 mL) and deionized water (0.9 mL) were then added and stirred at room temperature for about 1 minute. AgNO is added at one time 3 Aqueous solution (0.1 mL,0.4M in H) 2 O,0.04 mmol). The reaction was capped and stirred at 50 ℃ for 24 hours. The reaction was diluted with ethyl acetate (1 mL) and saturated NaHCO was added thereto 3 (3 mL). The crude product after spin-drying was extracted with ethyl acetate (3X 3 mL) and purified by column chromatography to give the desired product 3a (21 mg, 27%) as a brown oil. 1 H NMR(400MHz,CDCl 3 ):δ6.56(s,1H),5.89(s,1H),3.80(s,3H),2.64(ddd,J＝15.2,5.6,1.2Hz,1H),2.45(ddd,J＝14.8,5.2,1.2Hz,1H),1.39(d,J＝10.8Hz,2H),1.19(s,3H),0.87(s,3H),0.85(s,3H),0.78(s,3H)ppm； 13 C NMR(100MHz,CDCl 3 ):δ188.3,182.4,158.6,153.6,131.2,108.0,73.9,62.1,56.3(2C),44.8,41.8,40.6,39.6,33.5,33.4,25.0,24.0,21.6,20.5,18.6,15.4ppm.
Example 4: preparation of Compound 4 (4, see FIG. 3)
pTsOH (21 mg,0.12 mmol) was added to a solution of 3a (29 mg,0.08 mmol) in DCM (3 mL) and the mixture stirred at room temperature for 15 min before using saturated NaHCO 3 The aqueous solution was quenched and the crude product after spin-drying was purified by column chromatography to give compound 4 (26 mg, 93%) as an orange oil. 1 H NMR(400MHz,CDCl 3 ):δ6.17(s,1H),5.75(s,1H),2.63(d,J＝9.2Hz,2H),2.09(d,J＝11.1Hz,1H),1.80(d,J＝13.8Hz,1H),1.74-1.69(m,2H),1.64-1.60(m,3H),1.51-1.37(m,3H),1.33(s,3H),1.18(d,J＝13.8Hz,1H),1.02(d,J＝12.0Hz,1H),0.90(s,3H),0.86(s,3H),0.82(s,3H)ppm； 13 C NMR(100MHz,CDCl 3 ):δ180.3,178.7,165.2,145.2,128.3,107.8,82.0,55.7,51.5,41.5,40.5,38.5,37.0,33.2,33.1,23.5,21.9,21.3,19.5,18.1,14.6ppm.
Example 5: synthesis of (+) -8-epi-puupehenol (see FIG. 3)
Compound 4 (26 mg,0.08 mmol) was dissolved in EtOH (2 mL) and then NaBH was added 4 (6 mg,0.16 mmol). The mixture was stirred at room temperature for 20 minutes, then placed in a cold trap at 0 ℃, quenched by slow dropwise addition of dilute hydrochloric acid (2 naq.) until gas evolution ceased. Then diluted with EtOAc (15 mL) and spin-dried to give the crude compound (+) -8-epi-puupehenol.
Example 6: synthesis of (+) -8-epi-puupehedione (see FIG. 3)
The crude product (+) -8-epi-puupehenol was dissolved in t-butanol (2 mL) and 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ; 36mg,0.16 mmol) was added. After the resulting mixture was refluxed for 2 hours, the solvent was removed by concentration under reduced pressure. The residue was dissolved in ethyl acetate (10 mL) and the crude product after spin-drying was purified by column chromatography to give (+) -8-epi-puupehedione as a red solid (13 mg, 48% of total yield in two steps). 1 H NMR(400MHz,CDCl 3 ):δ6.26(s,1H),6.12(s,1H),5.92(s,1H),2.20(dd,J＝9.6,5.8Hz,1H),1.92-1.89(m,2H),1.82-1.72(m,2H),1.68-1.62(m,2H),1.58(s,3H),1.56-1.25(m,1H),1.47-1.40(m,2H),1.18(s,3H),1.10(d,J＝12.2Hz,1H),0.92(s,3H),0.89(s,3H)ppm； 13 C NMR(100MHz,CDCl 3 ):δ181.0,179.5,166.2,164.1,137.7,122.1,114.3,107.9,82.9,53.0,41.1,41.0,40.2,37.6,34.0,33.1,30.6,21.8,21.6,19.1,18.5ppm
Example 7: preparation of Compound 3b (3 b, see FIG. 4)
Carboxylate (0.2 mmol,1.0 equiv.), 2-methoxy-1, 4-benzoquinone (0.4 mmol,2.0 equiv.) and Selectfluor (142 mg,0.4mmol,2.0 equiv.) were added to the round bottom flask at room temperature. DCE (1 mL) and deionized water (0.9 mL) were then added and stirred at room temperature for about 1 minute. AgNO is added at one time 3 Aqueous solution (0.1 mL,0.4M in H) 2 O,0.04 mmol). The reaction was capped and stirred at 50 ℃ for 24 hours. The reaction was diluted with ethyl acetate (1 mL) and saturated NaHCO was added thereto 3 (3 mL). The crude product after spin-drying was extracted with ethyl acetate (3X 3 mL) and purified by column chromatography to give the desired product 3a (17 mg, 21%) as a brown oil. 1 H NMR(400MHz,CDCl 3 ):δ6.56(s,1H),5.89(s,1H),3.80(s,3H),2.64(ddd,J＝15.2,5.6,1.2Hz,1H),2.45(ddd,J＝14.8,5.2,1.2Hz,1H),1.39(d,J＝10.8Hz,2H),1.19(s,3H),0.87(s,3H),0.85(s,3H),0.78(s,3H)ppm； 13 C NMR(100MHz,CDCl 3 ):δ188.3,182.4,158.6,153.6,131.2,108.0,73.9,62.1,56.3(2C),44.8,41.8,40.6,39.6,33.5,33.4,25.0,24.0,21.6,20.5,18.6,15.4ppm.
Example 8: preparation of Compound 6 (6, see FIG. 4)
pTsOH (31 mg,0.18 mmol) was added to a solution of compound 3b (43 mg,0.12 mmol) in DCM (3 mL) at room temperature and after stirring for 15 min the solvent was evaporated in vacuo. The residue was purified by column chromatography to give compound 6 (37 mg, 94%) as an orange oil. 1 H NMR(400MHz,CDCl 3 ):δ6.55(s,1H),5.93(s,1H),3.81(s,3H),2.78(ddd,J＝18.7,6.1,1.3Hz,1H),2.40-2.38(m,1H),2.04(d,J＝18.9Hz,1H),1.76(dd,J＝11.2,3.4Hz,2H),1.55-1.51(m,3H),1.39-1.33(m,2H),1.30(dd,J＝6.0,3.1Hz,1H),1.15-1.07(m,1H),1.02(s,3H),0.97(s,3H),0.91-0.89(m,2H),0.87(s,3H)0.83(s,3H)ppm； 13 C NMR(100MHz,CDCl 3 ):δ187.2,182.3,158.4,153.0,130.4,107.8,72.8,57.3,56.2,56.1,42.5,41.8,39.9,39.0,33.4,33.3,31.3,30.8,23.1,21.7,18.2,15.2ppm
Example 9: preparation of the Natural product puupehedione (see FIG. 4)
Compound 6 (37 mg,0.12 mmol) was dissolved in EtOH (2 mL) and sodium borohydride (9 mg,0.24 mmol) was slowly added thereto at room temperature. The resulting mixture was stirred further, the reaction system was cooled to 0 ℃ and quenched by dropwise addition of dilute hydrochloric acid (2 naq.) until no gas evolved. The mixture was then diluted with ethyl acetate (15 mL) and dried by spin to give the crude compound puupehenol.
The crude product puupehenol was dissolved in 1, 4-dioxane (2 mL) and 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ; 54mg,0.24 mmol) was added. The resulting mixture was stirred under reflux for 2 hours, and then concentrated under reduced pressure to remove the solvent. The crude product was isolated by column chromatography to give puupehedione as a red solid (17 mg, 43% overall yield of the two steps). 1 H NMR(400MHz,CDCl 3 ):δ6.31(s,1H),6.12(s,1H),5.95(s,1H),2.09-2.06(m,1H),2.03-2.00(m,1H),1.88(d,J＝9.0Hz,1H),1.69(d,J＝14.4Hz,1H),1.60(d,J＝14.2Hz,1H),1.54(s,3H),1.47-1.46(m,1H),1.46-1.42(m,1H),1.32-1.29(m,1H),1.24(s,3H),1.13(d,J＝12.4Hz,1H),0.96(s,3H),0.89(s,3H)ppm； 13 C NMR(100MHz,CDCl 3 ):δ180.9,179.5,169.4,164.5,138.3,122.1,115.3,109.1,81.8,43.4,41.6,40.8,38.6,33.8,32.7,30.8,29.5,25.1,21.1,18.7,16.7ppm
Example 10: preparation of the natural product puupehenone (see FIG. 4)
Crude product 6 without purification was dissolved in CH 3 CN (2 mL)), to which K was added 2 CO 3 (10 mg,0.075 mmol) was stirred at room temperature for 1 hour, diluted with water (5 mL) and extracted with ethyl acetate (3X 5 mL). The crude product after spin-drying was purified by flash column chromatography on silica gel to give puupehenone (45 mg, 92%) as a yellow oil. 1 H NMR(400MHz,CDCl 3 ):δ6.88(s,br,1H),6.66(d,J＝6.9Hz,1H),6.20(s,1H),5.86(s,1H),2.17(dd,J＝2.4,11.4Hz,1H),2.04(d,J＝6.9Hz,1H),1.68(d,J＝6.9Hz,1H),1.23(s,3H),0.91(s,3H),0.85(s,3H),0.82(s,3H)ppm； 13 C NMR(100MHz,CDCl 3 ):δ182.1,162.8,147.5,140.4,129.4,106.1,105.1,78.9,54.9,53.9,41.7,40.8,40.1,39.3,33.7,33.3,28.1,21.9,18.5,18.1,15.0ppm
The present invention relates to the reaction of decarboxylation coupling reaction involving mild oxidant and silver catalyst to produce yahazunone active natural product, and the specific examples are preferred, but not limiting.
Claims (7)
1. A method for preparing marine terpene natural products based on deacidification coupling reaction of sclareolide carboxylate and benzoquinone compounds is characterized by comprising the following steps:
sclareolide carboxylate 1Or sclareolide carboxylic acid 1'>With benzoquinone compound 2->Under the action of a Selectfluor oxidant and a silver catalyst, minisci decarboxylation coupling reaction is carried out to generate a coupling product 3Or marine terpenoid natural product yahazunone->。
2. The method for preparing the marine terpene natural product based on deacidification coupling reaction of sclareolide carboxylate and benzoquinone compounds, which is characterized in that the coupling product 3 is subjected to subsequent functional group conversion and structural modification to prepare the marine terpene natural product.
3. The method for preparing the marine terpene natural product based on deacidification coupling reaction of sclareolide carboxylate and benzoquinone compounds, which is characterized in that the sclareolide carboxylate is selected from potassium salt, sodium salt and ammonium salt.
4. The method for preparing the marine terpene natural product based on deacidification coupling reaction of sclareolide carboxylate and benzoquinone compound, which is characterized in that the SelectFluor oxidant is SelectFluor or SelectFluor II.
5. The method for preparing the marine terpene natural product based on deacidification coupling reaction of sclareolide carboxylate and benzoquinone compound, which is characterized in that silver nitrate, silver phosphate, silver carbonate and silver fluoride are selected as catalysts by the silver catalyst.
6. The method for preparing the marine terpene natural product based on deacidification coupling reaction of sclareolide carboxylate and benzoquinone compound, as claimed in claim 1, wherein the decarboxylation coupling reaction process is characterized in that dichloroethane/water mixed solvent is selected as a reaction solvent.
7. The method for preparing the marine terpene natural product based on deacidification coupling reaction of sclareolide carboxylate and benzoquinone compounds, which is characterized in that the reaction temperature in the decarboxylation coupling reaction process is 20-50 ℃ and the reaction time is 20-40 hours.
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