CN110642906B - Total synthesis method of natural product coumarin tyramine glycoside compound - Google Patents
Total synthesis method of natural product coumarin tyramine glycoside compound Download PDFInfo
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- DZGWFCGJZKJUFP-UHFFFAOYSA-N Tyramine Natural products NCCC1=CC=C(O)C=C1 DZGWFCGJZKJUFP-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 229960003732 tyramine Drugs 0.000 title claims abstract description 26
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N benzo-alpha-pyrone Natural products C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 235000001671 coumarin Nutrition 0.000 title claims abstract description 25
- 229960000956 coumarin Drugs 0.000 title claims abstract description 25
- -1 coumarin tyramine glycoside compound Chemical class 0.000 title claims abstract description 25
- 229930182470 glycoside Natural products 0.000 title claims abstract description 22
- 238000000034 method Methods 0.000 title claims abstract description 18
- 238000006257 total synthesis reaction Methods 0.000 title claims abstract description 17
- 229930014626 natural product Natural products 0.000 title claims abstract description 7
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims abstract description 11
- 238000006206 glycosylation reaction Methods 0.000 claims abstract description 8
- AFDXODALSZRGIH-QPJJXVBHSA-N (E)-3-(4-methoxyphenyl)prop-2-enoic acid Chemical compound COC1=CC=C(\C=C\C(O)=O)C=C1 AFDXODALSZRGIH-QPJJXVBHSA-N 0.000 claims abstract description 6
- AFDXODALSZRGIH-UHFFFAOYSA-N p-coumaric acid methyl ether Natural products COC1=CC=C(C=CC(O)=O)C=C1 AFDXODALSZRGIH-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000006482 condensation reaction Methods 0.000 claims abstract description 5
- 229930182478 glucoside Natural products 0.000 claims abstract description 5
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 claims abstract description 4
- SHZGCJCMOBCMKK-JFNONXLTSA-N L-rhamnopyranose Chemical compound C[C@@H]1OC(O)[C@H](O)[C@H](O)[C@H]1O SHZGCJCMOBCMKK-JFNONXLTSA-N 0.000 claims abstract description 4
- PNNNRSAQSRJVSB-UHFFFAOYSA-N L-rhamnose Natural products CC(O)C(O)C(O)C(O)C=O PNNNRSAQSRJVSB-UHFFFAOYSA-N 0.000 claims abstract description 4
- 150000002148 esters Chemical class 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 239000003960 organic solvent Substances 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims description 10
- 230000035484 reaction time Effects 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical group [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 claims description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 239000002808 molecular sieve Substances 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- LNFJGCJNPDUWDR-BTVCFUMJSA-N (2R,3S,4R,5R)-2,3,4,5,6-pentahydroxyhexanal 2,2,2-trichloroacetamide Chemical compound OC(=N)C(Cl)(Cl)Cl.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O LNFJGCJNPDUWDR-BTVCFUMJSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 230000021736 acetylation Effects 0.000 claims description 4
- 238000006640 acetylation reaction Methods 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 4
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 4
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical group C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 claims description 4
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- YRGVFOFEUQMGQT-BZZIOBFNSA-N (e)-n-[2-[4-[(2s,3r,4r,5s,6s)-5-hydroxy-6-methyl-3,4-bis[[(2s,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy]oxan-2-yl]oxyphenyl]ethyl]-3-(4-methoxyphenyl)prop-2-enamide Chemical compound C1=CC(OC)=CC=C1\C=C\C(=O)NCCC(C=C1)=CC=C1O[C@H]1[C@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@@H](O)[C@H](C)O1 YRGVFOFEUQMGQT-BZZIOBFNSA-N 0.000 claims description 2
- LEEANUDEDHYDTG-UHFFFAOYSA-N 1,2-dimethoxypropane Chemical compound COCC(C)OC LEEANUDEDHYDTG-UHFFFAOYSA-N 0.000 claims description 2
- WLLIXJBWWFGEHT-UHFFFAOYSA-N [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate Chemical compound CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F WLLIXJBWWFGEHT-UHFFFAOYSA-N 0.000 claims description 2
- 229960000583 acetic acid Drugs 0.000 claims description 2
- 239000012362 glacial acetic acid Substances 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 125000005489 p-toluenesulfonic acid group Chemical group 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- YRGVFOFEUQMGQT-RDAJONLWSA-N teuvisside A Natural products COc1ccc(C=CC(=O)NCCc2ccc(O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)[C@H]3O[C@@H]5O[C@H](CO)[C@@H](O)[C@H](O)[C@H]5O)cc2)cc1 YRGVFOFEUQMGQT-RDAJONLWSA-N 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 4
- 230000004071 biological effect Effects 0.000 abstract description 2
- QWOJMRHUQHTCJG-UHFFFAOYSA-N CC([CH2-])=O Chemical compound CC([CH2-])=O QWOJMRHUQHTCJG-UHFFFAOYSA-N 0.000 abstract 2
- 150000001408 amides Chemical class 0.000 abstract 2
- 150000008131 glucosides Chemical class 0.000 abstract 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 abstract 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 abstract 1
- 238000007257 deesterification reaction Methods 0.000 abstract 1
- 238000010511 deprotection reaction Methods 0.000 abstract 1
- 239000008103 glucose Substances 0.000 abstract 1
- 230000013595 glycosylation Effects 0.000 abstract 1
- DZGWFCGJZKJUFP-UHFFFAOYSA-O tyraminium Chemical compound [NH3+]CCC1=CC=C(O)C=C1 DZGWFCGJZKJUFP-UHFFFAOYSA-O 0.000 abstract 1
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 16
- 239000011734 sodium Substances 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 238000012512 characterization method Methods 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 2
- UPQQXPKAYZYUKO-UHFFFAOYSA-N 2,2,2-trichloroacetamide Chemical compound OC(=N)C(Cl)(Cl)Cl UPQQXPKAYZYUKO-UHFFFAOYSA-N 0.000 description 2
- 208000004078 Snake Bites Diseases 0.000 description 2
- 230000002058 anti-hyperglycaemic effect Effects 0.000 description 2
- 239000003729 cation exchange resin Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- 230000008736 traumatic injury Effects 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- 241000058192 Chenopodiastrum hybridum Species 0.000 description 1
- 208000010445 Chilblains Diseases 0.000 description 1
- 206010017553 Furuncle Diseases 0.000 description 1
- 208000005577 Gastroenteritis Diseases 0.000 description 1
- 208000034507 Haematemesis Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 206010042674 Swelling Diseases 0.000 description 1
- 206010053476 Traumatic haemorrhage Diseases 0.000 description 1
- YLMHRWQPGGRXFQ-WLDMJGECSA-N [(3R,4S,5S,6R)-2,3,4,5-tetrahydroxy-6-(hydroxymethyl)oxan-2-yl] formate Chemical compound OC[C@H]1OC(O)(OC=O)[C@H](O)[C@@H](O)[C@@H]1O YLMHRWQPGGRXFQ-WLDMJGECSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 208000012873 acute gastroenteritis Diseases 0.000 description 1
- 210000001789 adipocyte Anatomy 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 208000001780 epistaxis Diseases 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 201000003453 lung abscess Diseases 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 238000000816 matrix-assisted laser desorption--ionisation Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 231100000611 venom Toxicity 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
Abstract
The invention discloses a total synthesis method of a natural product coumarin tyramine glycoside compound, belonging to the technical field of sugar chemistry. According to the invention, 4-methoxy cinnamic acid and tyramine which are cheap and easy to obtain are subjected to condensation reaction to obtain amide, the amide and rhamnose trichloroacetimido ester protected by total benzoyl are subjected to glycosylation reaction to obtain glucoside, and the glucoside is subjected to deesterification, acetonide protection of 2, 3-hydroxyl, acetyl protection of 4-hydroxyl, acetonide removal, glycosylation and deprotection with total benzoyl protection glucose trichloroacetimido ester to obtain a coumarin tyramine glucoside compound (Teuviside A). The method obtains the coumarin tyramine glycoside compound with total synthesis yield of 60%, has the advantages of cheap and easily-obtained raw materials, simple operation and high yield, and can provide a large amount of raw materials for biological activity research.
Description
Technical Field
The invention belongs to the technical field of carbohydrate chemistry, and particularly relates to a total synthesis method of a natural product coumarin tyramine glycoside compound (Teuviside A).
Background
Chenopodium hybridum is a perennial herb, is used as a medicine in all places, and is widely used for treating diseases such as rheumatic arthritis, traumatic injury, lung abscess, acute gastroenteritis, dyspepsia, chilblain swelling and pain, green pill defile swelling, hematemesis, epistaxis, traumatic hemorrhage, venomous snake bite, sore and furuncle. According to the book of Lingnan medicine collection: blood cooling and toxicity removing, stasis removing and tissue regeneration promoting, traumatic injury treating, sore application and toxin removing, snake bite treating and intestinal wind and bleeding eliminating. The coumarin tyramine glycoside compound as an active substance has better anti-hyperglycemic activity, and particularly the compound Teuviside A has obvious anti-hyperglycemic activity in liver cancer HepG2 cells and mouse embryo fibroblast 3T3-L1 fat cells (Journal of natural product 2014,77: 200-. However, because of its low content, it is difficult to separate and extract, and a large amount of the compound needs to be obtained by a chemical synthesis method to satisfy the subsequent biological activity research.
At present, no literature reports a total synthesis method of a natural product coumarin tyramine glycoside compound (Teuviside A), so that the development of an economic and efficient total synthesis method of the coumarin tyramine glycoside compound (Teuviside A) has important significance.
Disclosure of Invention
The invention aims to provide a total synthesis method of a coumarin tyramine glycoside compound (Teuviside A), which has the advantages of cheap and easily available raw materials, mild reaction conditions, simple operation and high yield.
Aiming at the purposes, the specific synthetic route and the synthetic method of the coumarin tyramine glucoside compound (Teuviside A) adopted by the invention are as follows:
1. 4-methoxy cinnamic acid and 4-hydroxy phenethylamine are subjected to condensation reaction to obtain 4-methoxy cinnamyl tyramide (intermediate 1).
2. Dissolving the intermediate 1 and the all-benzoyl protected rhamnose trichloroacetimidate in an organic solvent A, and adding
Carrying out glycosylation reaction on a molecular sieve and a catalyst under the protection of nitrogen to obtain the p-methoxy cinnamide 4-O-2',3',4' -tribenzoyl-O-L-pyranyl-rhamnoside (an intermediate 2).
3. Dissolving the intermediate 2 in an organic solvent B, adding an alkali reagent to remove benzoyl to obtain the p-methoxy cinnamide 4-O-L-pyran-rhamnoside (intermediate 3).
4. Adding the intermediate 3, 2-dimethoxypropane and p-toluenesulfonic acid into an organic solvent A, and performing selective propylidene and acetylation to obtain p-methoxy cinnamide 4-O-2',3' -O-propylidene-4 ' -O-acetyl-O-L-pyran-rhamnoside (intermediate 4).
5. Removing propylidene from the intermediate 4 by using an acidifying reagent to obtain the p-methoxy cinnamide 4-O-4' -O-acetyl-O-L-pyran-rhamnoside (intermediate 5).
6. Dissolving intermediate 5 and total benzoyl protected glucose trichloroacetimidate in organic solvent A, and adding
Carrying out glycosylation reaction on a molecular sieve and a catalyst under the protection of nitrogen to obtain p-methoxy cinnamamide 4-O- (2',3' -O-di-O-tetraphenyl formyl-O-D-glucopyranose) -4' -O-acetyl-O-L-pyran-rhamnoside (an intermediate 6).
7. And dissolving the intermediate 6 in an organic solvent B, and adding an alkali reagent to remove an ester group protecting group to obtain Teuvisside A, namely the coumarin tyramine glycoside compound.
In the step 1, 4-methoxy cinnamic acid and 4-hydroxy phenethylamine are subjected to condensation reaction at-10 to 50 ℃ under the action of 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide hydrochloric acid, 1-hydroxybenzotriazole and triethylamine, and are separated and purified after the reaction is finished to obtain an intermediate 1.
In the steps 2 and 6, the catalyst is trimethylsilyl trifluoromethanesulfonate or tert-butyldimethylsilyl trifluoromethanesulfonate, the temperature of the glycosylation reaction is-40 ℃ to room temperature, and the reaction time is 15-60 minutes.
In the step 3, the reaction temperature for removing the benzoyl on the intermediate 2 is 0-50 ℃, and the reaction time is 1-12 hours.
In the step 4, the reaction temperature of the selective propylidene and acetylation is 0-60 ℃, and the reaction time is 1-24 hours.
In the step 5, the acidifying reagent is p-toluenesulfonic acid, trifluoroacetic acid or glacial acetic acid, the reaction temperature for removing the propylidene is 0-100 ℃, and the reaction time is 1-12 hours.
In the steps 3 and 7, the alkali reagent is any one of sodium methoxide, potassium tert-butoxide, lithium hydroxide and sodium hydroxide.
In the step 7, the reaction temperature for removing the ester protecting group is 0-100 ℃, and the reaction time is 1-12 hours.
In the above steps 2, 4 and 6, the organic solvent a is dichloromethane, acetonitrile or a mixed solvent thereof.
In the above steps 3 and 7, the organic solvent B is one or more of dichloromethane, tetrahydrofuran, methanol, ethanol, and N, N-dimethylformamide.
The synthesis method of the coumarin tyramine glycoside compound (Teuviside A) has the following advantages:
1. the raw materials are cheap and easy to obtain, the reaction condition is mild, and the operation is simple.
2. The ester group is adopted as a protecting group, the removal is convenient and simple, and the linear total yield is higher and can reach 60 percent.
Detailed Description
The present invention will be described in further detail with reference to examples, but the scope of the present invention is not limited to these examples.
Example 1
1. 4-Methoxycinnamic acid (10g, 56.0mmol) was dissolved in 188mL of N, N-dimethylformamide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (11.84g, 62mmol) and 1-hydroxybenzotriazole (8.36g, 62mmol) were added successively at 0 ℃ and the reaction was stirred at 0 ℃ for 30 minutes, 4-hydroxyphenylethylamine (8.50g, 62mmol) and 16.4mL of triethylamine were added and the reaction was stirred for an additional 12 hours. After the thin layer detection reaction, the solvent was removed by concentration under reduced pressure, ethyl acetate and water were added for extraction, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography to obtain intermediate 1(15.8g) as a white solid with a yield of 95%.
The structural characterization data for the resulting intermediate 1 are:1H NMR(400MHz,CD3OD)δ8.33(br s,1H),7.47(m,3H),7.33(br s,1H),7.04(d,J＝8.3Hz,2H),6.93(d,J＝8.8Hz,2H),6.75(d,J＝8.3Hz,2H),6.55(d,J＝15.0Hz,1H),3.83(s,3H),3.46(q,J＝6.7Hz,2H),2.75(t,J＝7.3Hz,2H)；13C NMR(100MHz,CD3OD)δ166.3,161.9,156.3,139.7,131.0,130.3,130.0,128.9,120.4,116.0,115.3,55.9,42.3,35.3；MS(ESI)m/z:[M+H]+theoretical value 298.14, [ M + H]+Found 298.13.
2. Intermediate 1(10g, 33.5mmol) and all benzoyl protected rhamnose trichloroacetimidate (27.2g, 43.5mmol) were dissolved in 250mL of redistilled dry dichloromethane and 500mg were added
Adding trimethylsilyl trifluoromethanesulfonate (0.25mL) at 0 deg.C under nitrogen protection, maintaining the temperature, continuing to react for 1 hr, adding triethylamine to terminate the reaction, filtering to remove
Molecular sieve, reduced pressure concentration, silica gel column chromatography, obtained intermediate 2(22.8g) as a white solid in 90% yield.
The structural characterization data for the resulting intermediate 2 are:1HNMR(400MHz,CDCl3)δ6.89-8.16(m,24H,Ph-H),6.24(d,J＝15.6Hz,1H),6.07(dd,J＝10.4,3.2Hz,1H,H-3'),5.87(dd,J＝3.6,2.0Hz,1H,H-2'),5.79(t,J＝10.0Hz,1H,H-4'),5.74(d,J＝1.6Hz,1H,H-1'),4.35(m,1H,H-5'),3.84(s,3H,OMe),3.67(dd,J＝13.2,6.8Hz,2H),2.89(t,J＝13.6Hz,2H),1.37(t,J＝6.4Hz,3H,H-6')；13C NMR(100MHz,CDCl3)δ171.16,166.24,165.78,165.60,160.85,154.84,140.69,133.64,133.40,133.30,133.21,130.82,129.98,129.97,129.74,129.35,129.24,129.20,129.12,128.66,128.46,128.33,127.53,118.22,116.74,114.22,95.98,71.67,70.72,69.83,67.49,60.41,55.34,40.89,34.92,29.71,21.07,17.74,14.21；MS(ESI)m/z:[M+Na]+theoretical value 778.26, [ M + Na]+Found 801.27.
3. Dissolving the intermediate 2(8g, 10.6mmol) in 100mL of mixed solution of dichloromethane and methanol in a volume ratio of 1:1, adding sodium methoxide, adjusting the pH value to 9, stirring at room temperature for reaction for 2 hours, then adding a 731 type cation exchange resin for neutralization to neutrality, filtering, concentrating under reduced pressure, and carrying out silica gel column chromatography to obtain a white solid intermediate 3(4.60g) with the yield of 98%.
The structural characterization data for the resulting intermediate 3 are:1HNMR(100MHz,CD3OD)δ7.51(d,J＝8.8Hz,2H),7.47(br s,1H),7.18(d,J＝8.4Hz,2H),7.02(d,J＝8.8Hz,2H),6.96(d,J＝8.8Hz,2H),6.44(d,J＝16Hz,1H),5.40(d,J＝1.6Hz,1H,H-1'),4.00(dd,J＝3.2,1.6Hz,1H,H-2'),3.86(dd,J＝9.2,3.2Hz,1H,H-3'),3.84(s,3H,OMe),3.66(m,1H,H-5'),3.51(dd,J＝15.2,7.2Hz,2H),2.83(t,J＝7.2Hz,2H),1.23(t,J＝6.4Hz,3H,H-6')；13C NMR(100MHz,CD3OD)δ167.65,161.18,155.07,140.04,132.88,130.65,129.44,128.99,128.91,127.46,117.86,116.23,113.93,113.16,98.57,72.46,70.84,70.71,69.16,54.42,40.95,34.40,16.63；MS(ESI)m/z:[M+H]+theoretical value 444.10, [ M + H]+Found 444.12.
4. Intermediate 3(3.2g, 7.20mmol), 2-dimethoxypropane (10mL) and p-toluenesulfonic acid (14mg) were dissolved in 20mL of dry anhydrous dichloromethane, reacted at room temperature for 5 hours, and then washed with saturated aqueous sodium bicarbonate solution and saturated brine in this order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was dissolved in 20mL of dry anhydrous dichloromethane, triethylamine (1mL) and acetic anhydride (5mL) were added at 0 ℃ and allowed to react at room temperature for 2 hours, followed by concentration under reduced pressure and silica gel column chromatography to give intermediate 4(3.37g) as a white solid with a yield of 89%.
The structural characterization data for intermediate 4 obtained are:1HNMR(100MHz,CDCl3)δ7.44(d,J＝8.0Hz,2H),7.42(br s,1H),7.16(d,J＝8.0Hz,2H),6.99(d,J＝8.4Hz,2H),6.88(d,J＝8.4Hz,2H),6.66(d,J＝12.4Hz,1H),5.67(brs,1H,H-1'),4.36(t,J＝5.6Hz,1H,H-2'),4.24(dd,J＝9.2,3.2Hz,1H,H-3'),3.83(s,3H,OMe),3.77(m,1H,H-5'),3.62(t,J＝6.8Hz,1H),3.50(t,J＝9.2Hz,1H,H-4'),3.45(m,2H),2.84(t,J＝6.8Hz,1H),1.58,1.42(s each,3H each,CH3×2),1.25(t,J＝6.3Hz,3H,H-6')；13C NMR(100MHz,CDCl3)δ167.38,159.90,154.91,136.33,130.75,129.87,129.69,129.33,127.48,122.55,116.68,116.57,114.22,113.76,109.74,95.61,78.46,75.84,74.39,66.64,55.31,40.44,34.44,28.03,26.29,17.36；MS(ESI)m/z:[M+Na]+theoretical value 548.23, [ M + Na]+Found 548.21.
5. Intermediate 4(2.30g, 3.6mmol) and trifluoroacetic acid (2.5mL) were dissolved in 50mL of methanol, reacted at room temperature for 4 hours, quenched by the addition of 10mL of triethylamine, extracted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and saturated brine in that order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to silica gel column chromatography to give intermediate 5(1.59g) as a white solid in 91% yield.
The structural characterization data for intermediate 5 obtained are:1H NMR(100MHz,CD3OD)δ7.51(d,J＝8.0Hz,2H),7.46(br s,1H),7.21(d,J＝8.4Hz,2H),7.04(d,J＝8.4Hz,2H),6.95(d,J＝8.8Hz,2H),6.44(d,J＝16.0Hz,1H),5.43(brs,1H,H-1'),5.02(t,J＝6.6Hz,1H,H-4'),4.03(dd,J＝10.0,4.4Hz,1H,H-3'),3.84(s,3H,OMe),3.78(m,2H,H-2',H-5'),3.52(t,J＝7.2Hz,2H),2.84(t,J＝6.8Hz,2H),2.10(s,3H,CH3),1.12(t,J＝6.8Hz,3H,H-6')；13C NMR(100MHz,CD3OD)δ171.02,167.64,161.18,154.91,140.04,133.06,130.66,129.50,128.99,127.45,117.84,116.20,116.14,98.43,73.93,70.70,68.81,67.02,54.42,40.92,34.41,19.59,16.45；MS(ESI)m/z:[M+Na]+theoretical value 508.19, [ M + Na]+Found 508.20.
6. Intermediate 5(1g, 2.06mmol) and total benzoyl protected glucose trichloroacetimidate (9.16g, 12.4mmol) were dissolved in 100mL of redistilled dry anhydrous dichloromethane and 100mg of total benzoyl protected glucose trichloroacetimidate was added
Adding trimethylsilyl trifluoromethanesulfonate (0.10mL) at 0 deg.C under nitrogen protection, maintaining the temperature, continuing to react for 1 hr, adding triethylamine to terminate the reaction, filtering to remove
Molecular sieves, concentration under reduced pressure, and silica gel column chromatography gave intermediate 6(3.11g) as a white solid in 93% yield.
The structural characterization data for intermediate 6 obtained are: MS (MALDI) M/z [ M + Na ]]+Theoretical value 1664.51, [ M + Na]+Found 1664.53.
7. Dissolving the intermediate 6(1.2g, 0.07mmol) in 20mL of mixed solution of dichloromethane and methanol in a volume ratio of 1:1, adding sodium methoxide, adjusting the pH value to 9, stirring at room temperature for reaction for 2 hours, then adding type 731 cation exchange resin for neutralization to neutrality, filtering, concentrating under reduced pressure, and performing silica gel column chromatography to obtain a white solid coumarin tyramine glycoside compound (0.53g) with a yield of 95%.
The structural characterization data of the obtained coumarin tyramine glycoside compound are as follows:1HNMR(100MHz,CD3OD)δ7.50(d,J＝8.5Hz,2H),7.48(d,J＝15.5Hz,1H),7.19(d,J＝8.5Hz,2H),7.04(d,J＝8.5Hz,2H),6.95(d,J＝8.5Hz,2H),6.44(d,J＝15.5Hz,1H),5.86(d,J＝8.0Hz,1H,H-1”),4.53(d,J＝8.0Hz,1H,H-1”'),4.49(d,J＝1.5Hz,1H,H-1'),4.07(br s,1H,H-2'),3.92(dd,J＝9.0,3.0Hz,1H,H-3”),3.91(d,J＝12.0Hz,1H,H-6”-1),3.85(d,J＝12.0Hz,1H,H-6”'-1),3.84(s,3H,OMe),3.78(dd,J＝12.0,5.0Hz,1H,H-6”-2),3.68(m,H-5'),3.63(t,J＝9.5Hz,1H,H-4'),3.62(dd,J＝12.0,5.0Hz,1H,H-6”'-2),3.51(t,J＝7.5Hz,2H),3.41-3.51(m,6H,H-2”,H-3”,H-4”,H-2'",H-3'",H-4'"),3.42(t,J＝9.0Hz,1H,H-3”),3.36(t,J＝9.0Hz,1H,H-3"'),2.83(t,J＝7.5Hz,2H),1.22(d,J＝5.5Hz,3H,H-6')；13C NMR(100MHz,CD3OD)δ169.2,162.7,156.4,141.5,134.5,130.9,130.5,128.9,119.4,117.8,115.4,106.8,105.5,98.9,82.7,81.7,78.4,78.2,78.0,76.1,75.6,72.5,71.7,71.5,69.3,62.9,62.7,55.9,42.4,35.9,18.3；MS(ESI)m/z:[M+Na]+theoretical value 790.29, [ M + Na]+Found 790.28.
Claims (9)
1. A total synthesis method of a natural product coumarin tyramine glucoside compound is characterized by comprising the following steps:
(1) carrying out condensation reaction on 4-methoxy cinnamic acid and 4-hydroxy phenethylamine to obtain an intermediate 1;
(2) reacting intermediate 1 with benzoylDissolving the protected rhamnose trichloroacetimido ester in an organic solvent A, and adding
Carrying out glycosylation reaction on a molecular sieve and a catalyst under the protection of nitrogen to obtain an intermediate 2;
(3) dissolving the intermediate 2 in an organic solvent B, and adding an alkali reagent to remove benzoyl to obtain an intermediate 3;
(4) adding the intermediate 3, 2-dimethoxypropane and p-toluenesulfonic acid into an organic solvent A, and performing selective propylidene and acetylation to obtain an intermediate 4;
(5) removing propylidene from the intermediate 4 by using an acidifying reagent to obtain an intermediate 5;
(6) dissolving intermediate 5 and total benzoyl protected glucose trichloroacetimidate in organic solvent A, and adding
Carrying out glycosylation reaction on a molecular sieve and a catalyst under the protection of nitrogen to obtain an intermediate 6;
(7) and dissolving the intermediate 6 in an organic solvent B, and adding an alkali reagent to remove an ester group protecting group to obtain Teuvisside A, namely the coumarin tyramine glycoside compound.
2. The total synthesis method of a coumarin tyramine glycoside compound according to claim 1, characterized in that: in the step (1), 4-methoxy cinnamic acid and 4-hydroxy phenethylamine are subjected to condensation reaction at-10-50 ℃ under the action of 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide hydrochloric acid, 1-hydroxybenzotriazole and triethylamine, and are separated and purified after the reaction is finished to obtain an intermediate 1.
3. The total synthesis method of coumarin tyramine glycoside compounds according to claim 1, characterized in that: in the steps (2) and (6), the catalyst is trimethylsilyl trifluoromethanesulfonate or tert-butyldimethylsilyl trifluoromethanesulfonate, the temperature of the glycosylation reaction is-40 ℃ to room temperature, and the reaction time is 15-60 minutes.
4. The total synthesis method of a coumarin tyramine glycoside compound according to claim 1, characterized in that: in the step (3), the reaction temperature for removing the benzoyl on the intermediate 2 is 0-50 ℃, and the reaction time is 1-12 hours.
5. The total synthesis method of a coumarin tyramine glycoside compound according to claim 1, characterized in that: in the step (4), the reaction temperature of selective propylidene and acetylation is 0-60 ℃, and the reaction time is 1-24 hours.
6. The total synthesis method of a coumarin tyramine glycoside compound according to claim 1, characterized in that: in the step (5), the acidifying reagent is p-toluenesulfonic acid, trifluoroacetic acid or glacial acetic acid, the reaction temperature for removing the propylidene is 0-100 ℃, and the reaction time is 1-12 hours.
7. The total synthesis method of a coumarin tyramine glycoside compound according to claim 1, characterized in that: in the steps (3) and (7), the alkali reagent is any one of sodium methoxide, potassium tert-butoxide, lithium hydroxide and sodium hydroxide.
8. The total synthesis method of a coumarin tyramine glycoside compound according to claim 1, characterized in that: in the step (7), the reaction temperature for removing the ester protecting group is 0-100 ℃, and the reaction time is 1-12 hours.
9. The total synthesis method of a coumarin tyramine glycoside compound according to claim 1, characterized in that: in the steps (2), (4) and (6), the organic solvent A is dichloromethane, acetonitrile or a mixed solvent thereof; in the steps (3) and (7), the organic solvent B is one or more of dichloromethane, tetrahydrofuran, methanol, ethanol and N, N-dimethylformamide.
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