CN115010717B - Full-synthesis preparation method of lycorine (+ -) -alpha-lycorane - Google Patents
Full-synthesis preparation method of lycorine (+ -) -alpha-lycorane Download PDFInfo
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- CN115010717B CN115010717B CN202210643011.6A CN202210643011A CN115010717B CN 115010717 B CN115010717 B CN 115010717B CN 202210643011 A CN202210643011 A CN 202210643011A CN 115010717 B CN115010717 B CN 115010717B
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- XGVJWXAYKUHDOO-DANNLKNASA-N lycorine Chemical compound C1CN2CC3=CC=4OCOC=4C=C3[C@H]3[C@H]2C1=C[C@H](O)[C@H]3O XGVJWXAYKUHDOO-DANNLKNASA-N 0.000 title claims abstract description 19
- XGVJWXAYKUHDOO-UHFFFAOYSA-N galanthidine Natural products C1CN2CC3=CC=4OCOC=4C=C3C3C2C1=CC(O)C3O XGVJWXAYKUHDOO-UHFFFAOYSA-N 0.000 title claims abstract description 18
- KQAOMBGKIWRWNA-UHFFFAOYSA-N lycorine Natural products OC1C=C2CCN3C2C(C1O)c4cc5OCOc5cc34 KQAOMBGKIWRWNA-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims description 6
- 238000003786 synthesis reaction Methods 0.000 title description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 54
- 238000006257 total synthesis reaction Methods 0.000 claims abstract description 15
- 150000001540 azides Chemical class 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 12
- QFQYZMGOKIROEC-DUXPYHPUSA-N Methylenedioxycinnamic acid Chemical compound OC(=O)\C=C\C1=CC=C2OCOC2=C1 QFQYZMGOKIROEC-DUXPYHPUSA-N 0.000 claims abstract description 8
- QFQYZMGOKIROEC-UHFFFAOYSA-N Piperonylideneacetic acid Natural products OC(=O)C=CC1=CC=C2OCOC2=C1 QFQYZMGOKIROEC-UHFFFAOYSA-N 0.000 claims abstract description 8
- SAXBDVYNGGCITG-ONEGZZNKSA-N (3e)-hexa-3,5-dien-1-ol Chemical compound OCC\C=C\C=C SAXBDVYNGGCITG-ONEGZZNKSA-N 0.000 claims abstract description 7
- 238000006290 Diels-Alder intramolecular cycloaddition reaction Methods 0.000 claims abstract description 5
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims abstract description 3
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 3
- 238000006722 reduction reaction Methods 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 28
- 239000013067 intermediate product Substances 0.000 claims description 25
- 239000011261 inert gas Substances 0.000 claims description 21
- -1 lactone compound Chemical class 0.000 claims description 21
- 239000000047 product Substances 0.000 claims description 12
- 230000003197 catalytic effect Effects 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 10
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- 239000002994 raw material Substances 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 238000011065 in-situ storage Methods 0.000 claims description 5
- BCJVBDBJSMFBRW-UHFFFAOYSA-N 4-diphenylphosphanylbutyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCCP(C=1C=CC=CC=1)C1=CC=CC=C1 BCJVBDBJSMFBRW-UHFFFAOYSA-N 0.000 claims description 3
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 150000001263 acyl chlorides Chemical class 0.000 claims description 3
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 claims description 3
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical compound OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 238000006923 Schmidt rearrangement reaction Methods 0.000 claims description 2
- 230000003213 activating effect Effects 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- YNLAOSYQHBDIKW-UHFFFAOYSA-M diethylaluminium chloride Chemical compound CC[Al](Cl)CC YNLAOSYQHBDIKW-UHFFFAOYSA-M 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- 239000002808 molecular sieve Substances 0.000 claims description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 2
- 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 2
- 238000006085 Schmidt reaction Methods 0.000 abstract description 2
- 239000002246 antineoplastic agent Substances 0.000 abstract description 2
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 2
- 230000001737 promoting effect Effects 0.000 abstract description 2
- 238000005886 esterification reaction Methods 0.000 abstract 1
- NJNVJNIQKKBKJQ-UHFFFAOYSA-N phenanthridine;1h-pyrrole Chemical group C=1C=CNC=1.C1=CC=C2C3=CC=CC=C3C=NC2=C1 NJNVJNIQKKBKJQ-UHFFFAOYSA-N 0.000 abstract 1
- 230000001766 physiological effect Effects 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 25
- 239000011734 sodium Substances 0.000 description 17
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 229930013930 alkaloid Natural products 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 241001633628 Lycoris Species 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- 230000000171 quenching effect Effects 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000000824 cytostatic agent Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 230000005918 in vitro anti-tumor Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- 241000234479 Narcissus Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241001145025 Saussurea involucrata Species 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/16—Peri-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- 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
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
-
- 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
Abstract
The invention belongs to the technical field of organic synthetic chemistry, and discloses a novel method for preparing lycorine (+ -) -alpha-lycorane and (+ -) -lycorine through total synthesis. The target molecule (+ -) -alpha-lycorane is synthesized by taking 3, 5-hexadien-1-ol and 3,4- (methylenedioxy) cinnamic acid as starting materials, sequentially carrying out esterification reaction, intramolecular Diels-Alder reaction, bromoring opening, azide reaction, propargyl removal reaction, intramolecular Schmidt reaction, hydrogenation reaction and reduction reaction. The Lycorine alkaloid has a four-ring structure, mainly takes a pyrrole-phenanthridine ring as a basic skeleton, and has important physiological activity. The novel method for preparing lycorine (+ -) -alpha-lycorane by total synthesis is more concise and effective, and creates conditions for promoting lycorine to be used as a good anti-tumor drug.
Description
Technical Field
The invention relates to the field of organic chemistry, in particular to a total synthesis preparation method of lycorine (+ -) -alpha-lycorane.
Background
Lycoris plants have been used as ornamental plants, in particular narcissus and saussurea involucrata, and at the same time, alkaloids isolated from lycoris plants have various biological activities, including antitumor, antibacterial, antifungal, antimalarial, antiviral, analgesic and AChE inhibitory activities. Up to now, the in vitro antitumor activity of 22 lycoris alkaloids against four cancer lines has been studied, and lycorane showed the highest in vitro antitumor potential among the alkaloids studied, with (+ -) - α -lycorane proved to be a cytostatic and cytostatic agent. Because of the remarkable biological activity of lycoris alkaloids, the development of a concise and efficient synthetic route is particularly important.
Lcorine alkaloids mainly take a pyrrolofilidine ring as a core skeleton, and because of the remarkable biological activity, synthesis research of the Lcorine alkaloids is also widely focused, but how to complete the synthesis of (+/-) -alpha-lycorane by a simple and efficient synthesis route is a problem to be solved for the long synthesis route of (+/-) -alpha-lycorane (refer to Org. Lett.2013,15, 132-135).
Disclosure of Invention
The invention aims to provide a simple and effective novel method for preparing lycorine (+ -) -alpha-lycorane by total synthesis.
The invention is realized by the following technical scheme:
the invention relates to a total synthesis preparation method of lycorine (+ -) -alpha-lycorane, which comprises the following steps:
step a, 3,4- (methylenedioxy) cinnamic acid and 3, 5-hexadien-1-ol are used as raw materials to react to generate 3, 5-diene-1-hydroxybenzo-1, 3-dioxol-5-yl acrylate;
step b, taking 3, 5-diene-1-hydroxybenzo-1, 3-dioxole-5-yl acrylate as a raw material, and carrying out intramolecular Diels-Alder reaction to generate a lactone compound;
step c, performing bromoring opening on the lactone compound to generate a bromocompound;
step d, performing an azide reaction on the brominated compound to generate an azide intermediate product;
step e, performing a propargyl removal reaction on the azide intermediate product to generate omega-azidocarboxylic acid compounds;
f, activating omega-azido carboxylic acid compound in situ by oxalyl chloride, and catalyzing by boron trifluoride diethyl ether to obtain a catalysis intermediate product;
step g, catalyzing the intermediate product to carry out a schmidt rearrangement reaction to generate a four-ring product;
and h, performing hydrogenation and carbonyl reduction reaction on the four-ring product to complete the total synthesis of (+ -) -alpha-lycorane.
Preferably, the step a specifically includes: under the protection of inert gas, dissolving 3,4- (methylenedioxy) cinnamic acid and dichloromethane in a reaction vessel; sequentially adding N, N' -dicyclohexylcarbodiimide, 4-dimethylaminopyridine and 3, 5-hexadien-1-ol; the reaction is carried out to generate 3, 5-diene-1-hydroxybenzo-1, 3-dioxacyclopentene-5-yl acrylic ester, and then the acrylic ester is collected.
Preferably, the step b includes: under the protection of inert gas, firstly adding the baked 4A molecular sieve into a reaction container, then sequentially adding 3, 5-diene-1-hydroxybenzo-1, 3-dioxol-5-yl acrylate and anhydrous toluene solution, and fully dissolving; diethyl aluminum chloride is added into the system at the temperature of 0 ℃, the mixture is heated to generate intramolecular Diels-Alder reaction, and lactone compounds are collected.
Preferably, the step c includes: under the protection of inert gas, adding a lactone compound into a reaction container; dissolving a lactone compound with dichloromethane; adding propargyl alcohol at room temperature; adding trimethyl bromosilane at 0 ℃; the brominated compound is generated by reaction and then collected.
Preferably, the step d includes: dissolving a bromo compound in N, N-dimethylformamide; adding sodium azide, and then heating to an external oil bath of 40 ℃ for reaction; the reaction is carried out to generate an azide intermediate product, and the azide intermediate product is collected.
Preferably, the step e includes: under the protection of inert gas, palladium acetate, 1, 4-bis (diphenylphosphine) butane and acetonitrile are added into a reaction container; heating to 80 ℃, stirring until the solution is clear, and then cooling to room temperature; adding triethylamine and an azidation intermediate product, and reacting at 30 ℃; the omega-azidocarboxylic acid compound is obtained after reaction and collected.
Preferably, the step f includes: under the protection of inert gas, adding omega-azido carboxylic acid compound and methylene dichloride into a reaction container, and dissolving; after oxalyl chloride is added under the room temperature condition, the temperature is raised to 30 ℃ to prepare the acyl chloride in situ; adding boron trifluoride diethyl etherate under ice bath condition, and heating to 40 ℃ for reaction; the reaction is carried out to generate a catalytic intermediate product, and then the catalytic intermediate product is collected.
Preferably, the step g includes: under the protection of inert gas, adding a catalytic intermediate product into a reaction container, and dissolving the catalytic intermediate product with ethanol; then adding platinum dioxide and introducing hydrogen into the reaction system; the four-membered ring product is generated after the reaction and then collected.
Preferably, the step h includes: under the protection of inert gas, adding a four-ring product into a reaction container; dissolving with tetrahydrofuran, and adding lithium aluminum hydride under ice bath condition; after the system is restored to room temperature, the temperature is raised to 60 ℃ to react to generate (+ -) -alpha-lycorane, and the (+ -) -alpha-lycorane is collected.
The invention has the beneficial effects that: the invention takes 3, 5-hexadiene-1-alcohol and 3,4- (methylenedioxy) cinnamic acid as initial raw materials, and prepares lycorine (+/-) -alpha-lycorane with remarkable biological activity through eight steps of synthesis.
Compared with the existing synthetic route, the method has the following advantages:
a) The 3, 5-hexadien-1-ol and 3,4- (methylenedioxy) cinnamic acid which are required by synthesis are cheap and easy to obtain, and the cost is cheap and controllable.
b) The conditions of each step of chemical reaction are mild, and the operation is easy to implement in practical application.
c) The ring-forming strategy is simple and effective, and particularly, the Schmidt reaction can simultaneously construct two rings in one step, and the total yield of the reaction reaches 11%.
In conclusion, the novel method for preparing the lycorine (+ -) -alpha-lycorane by total synthesis is more concise and effective, and creates a necessary condition for promoting lycorine to be used as a good anti-tumor drug development.
Drawings
Fig. 1: the synthetic route of the invention is schematically shown;
Detailed Description
The invention is further described in connection with the following embodiments:
examples: a total synthesis preparation method of lycorine (+ -) -alpha-lycorane comprises the following steps:
a. 3,4- (methylenedioxy) cinnamic acid (16.5 mmol,3.2 g) was added to a dry 100mL round bottom flask under inert gas followed by dissolution in 60mL of dichloromethane;
DCC (22.5 mmol,4.6 g) and DMAP (1.5 mmol,183 mg) were added separately at room temperature; finally 3, 5-hexadien-1-ol (15 mmol,1.5 g) was added;
after 4h of reaction, the mixture was directly filtered and concentrated, and the target product 3, 5-diene-1-hydroxybenzo-1, 3-dioxol-5-yl acrylate (3.5 g, yield 85%) was obtained as a white solid by flash column chromatography separation. R is R f ＝0.75(EtOAc/PE＝1/5)； 1 H NMR(CDCl 3 ,400MHz)δ7.58(d,J＝16.0Hz,1H),7.18–6.87(m,2H),6.79(d,J＝8.0Hz,1H),6.46–6.08(m,3H),5.99(s,2H),5.70(dt,J＝14.7,7.0Hz,1H),5.14(dd,J＝16.9,1.7Hz,1H),5.04–4.98(m,1H),4.23(t,J＝6.8Hz,2H),2.48(qd,J＝6.9,1.4Hz,2H). 13 C NMR(CDCl 3 ,100MHz,plus,APT)δ(up)167.2,149.7,148.4,128.9,116.2,101.6,63.7,32.1；δ(down)144.6,136.9,133.5,129.9,124.6,116.0,108.6,106.6；IR(film)2897,1705,1630,1492cm -1 ；HRMS(FTMS-ESI)m/z[M+Na] + calcd for C 16 H 16 O 4 Na 295.0941,found 295.0933.
b. Adding baked 4A-MS (1.5 g) into a dried round bottom flask under the protection of inert gas, and adding 3, 5-diene-1-hydroxybenzo-1, 3-dioxol-5-yl acrylate (4 mmol,1.09 g) prepared in the step a under the protection of nitrogen gas;
dissolving with 130mL of anhydrous toluene solution, adding Et to the system at 0deg.C 2 AlCl (1.5 mmol,3 mL) was then warmed to 100deg.C and stirred, after which the reaction was stopped after 30h of stirring;
when the temperature of the system is restored to room temperature, saturated sodium bicarbonate is slowly added for quenching reaction, filtering, extraction by ethyl acetate, and saturated saline water washing and anhydrous Na after the organic phase is combined 2 SO 4 Drying, concentrating, and separating by rapid column chromatography to obtain the target lactone compound as white solid with a yield of 71%.
R f ＝0.48(EtOAc/PE＝1/3)； 1 H NMR(CDCl 3 ,400MHz)δ6.80(s,1H),6.74(d,J＝2.4Hz,2H),6.12–5.98(m,1H),5.92(s,2H),5.67–5.58(m,1H),4.59–4.06(m,2H),3.80(dd,J＝7.0,3.2Hz,1H),2.67(dd,J＝6.2,3.3Hz,1H),2.64–2.51(m,1H),2.51–2.42(m,1H),2.32–2.18(m,1H),2.10–1.95(m,1H),1.83–1.71(m,1H). 13 C NMR(CDCl 3 ,100MHz,plus,APT)δ(up)172.2,147.6,145.6,137.5,100.9,66.6,28.1,26.0,δ(down)129.6,128.2,120.3,108.1,107.8,45.0,37.2,27.2；IR(film)2903,1726,1610,1492cm -1 ；HRMS(FTMS-ESI)m/z[M+Na] + calcd for C 16 H 16 O 4 Na 295.0941,found 295.0934.
c. The lactone compound (5 mmol,1.35 g) prepared in step b was added to a dry 50mL reaction tube under inert gas, and dissolved in 25mL of methylene chloride;
propargyl alcohol (10 mmol,3.0 mL) was added at room temperature, TMSBr (25 mmol,3.3 mL) was added at 0deg.C, and the system was returned to room temperature and stirred;
TLC tracking monitoring reaction 72h complete raw material reaction, adding water quenching, dichloromethane extraction, combining organic phases, washing with sodium thiosulfate solution, then saturated saline water washing, anhydrous Na 2 SO 4 Drying, concentrating, and separating by rapid column chromatography to obtain brominated compound as colorless liquid with a yield of 81%.
Rf＝0.71(EtOAc/PE＝1/3)； 1 H NMR(CDCl 3 ,400MHz)δ6.88–6.48(m,3H),5.92(s,2H),5.86–5.78(m,2H),5.09–4.22(m,2H),3.58–3.48(m,1H),3.47–3.35(m,1H),3.15–2.99(m,2H),2.83–2.78(m,1H),2.52–2.33(m,2H),2.16–1.90(m,3H). 13 C NMR(CDCl 3 ,100MHz,plus,APT)δ(up)171.8,147.4,145.4,138.4,100.7,74.9,74.8,50.9,34.9,34.1,31.6.δ(down)127.2,127.1,120.3,108.1,107.4,48.3,37.5,34.8；IR(film)3290,2912,1741,1491cm -1 ；HRMS(FTMS-ESI)m/z[M+Na] + calcd for C 19 H 19 BrO 4 Na 413.0359,found 413.0344.
d. The bromo compound (0.26 mmol,102 mg) prepared in step c was dissolved in 1.5mL DMF, sodium azide (0.52 mmol,34 mg) was added, then the reaction system was warmed to 40 ℃ in external oil bath, reacted for 8h, and then water quenched;
extracting with ethyl acetate, mixing the organic phases, washing with water, saturated salt water, and anhydrous Na 2 SO 4 And (3) drying, concentrating, and separating by rapid column chromatography to obtain an azide intermediate product which is colorless liquid with the yield of 89%.
Rf＝0.71(EtOAc/PE＝1/3)； 1 H NMR(CDCl 3 ,400MHz)δ6.79–6.61(m,3H),5.90(s,2H),5.81–5.77(m,2H),4.74–4.39(m,2H),3.46–3.24(m,2H),3.16–3.00(m,2H),2.75–2.61(m,1H),2.48–2.32(m,2H),2.14–2.01(m,1H),1.84–1.61(m,2H). 13 C NMR(CDCl 3 ,100MHz,plus,APT)δ(up)171.8,147.7,146.0,138.2,100.2,75.0(2),51.3,49.4,34.3,31.4.δ(down)127.6,127.3,120.3,108.3,107.7,48.7,37.5,33.9；IR(film)3290,2936,2099,1739,1492cm -1 ；HRMS(FTMS-ESI)m/z[M+Na] + calcd for C 19 H 19 N 3 O 4 Na 376.1268,found 376.1267.
e. Pd (OAc) was added to the reaction tube under inert gas 2 (10% mmol,6.7 mg) and 1, 4-bis (diphenylphosphine) butane (20% mmol,26 mg);
then adding 2mL of acetonitrile, heating to 80 ℃ and stirring, and closing the heating after the system becomes clear;
after the reaction system was cooled to room temperature, triethylamine (8 mmol,0.33 ml) and the azide intermediate (0.3 mmol,110 mg) prepared in step d were added, and the reaction was stirred at 30 ℃ for 48 hours and then completed;
then directly concentrating and then separating by rapid column chromatography to obtain omega-azidocarboxylic acid compound as colorless liquid with the yield of 55%.
Rf＝0.38(EtOAc/PE＝1/3)； 1 H NMR(CDCl 3 ,400MHz)δ11.0(brs,1H),6.84–6.53(m,3H),5.92(s,2H),5.84–5.68(m,2H),3.46–3.21(m,2H),3.04(d,2H),2.62(s,1H),2.39(d,J＝19.9Hz,1H),2.11–2.02(m,1H),1.83–1.62(m,2H). 13 C NMR(CDCl 3 ,100MHz,plus,APT)δ(up)179.1,147.6,146.0,138.6,100.9,49.3,33.8,30.9.；δ(down)127.6,127.2,120.2,108.3,107.6,48.7,37.4,33.6；IR(film)2891,2098,1707cm -1 ；HRMS(FTMS-ESI)m/z[M+Na] + calcd for C 16 H 17 N 3 O 4 Na 338.1111,found 338.1101.
f. Under the protection of inert gas, adding the omega-azidocarboxylic acid compound (0.42 mmol,133 mg) prepared in the step e into a reaction tube, dissolving in 2mL of dichloromethane, adding oxalyl chloride (0.59 mmol,0.05 mL) at room temperature, heating the reaction system to 30 ℃ and stirring for 1.5 hours to prepare the acyl chloride in situ;
the BF is then added under ice bath conditions 3 ·OEt 2 (0.84 mmol,0.25 mL) and the reaction system was warmed to 40deg.C and stirred for 66h;
then slowly drop saturated NaHCO 3 The solution was quenched, the mixture was extracted with ethyl acetate, the organic phases were combined, washed with saturated aqueous experimental water, anhydrous Na 2 SO 4 The catalytic intermediate product was obtained as a yellow solid in 65% yield by flash column chromatography after drying and concentration.
R f ＝0.29(EtOAc/PE＝1/1)； 1 H NMR(CDCl 3 ,400MHz)δ7.47(s,1H),6.67(s,1H),5.99(s,2H),5.96–5.83(m,2H),4.18(dd,J＝11.8,7.3Hz,1H),3.64(dd,J＝12.8,8.9Hz,1H),3.29(td,J＝11.9,5.3Hz,1H),2.91–2.85(m,1H),2.69(td,J＝12.2,4.7Hz,1H),2.53(dt,J＝16.8,5.3Hz,1H),2.22–2.12(m,1H),2.07–1.92(m,1H),1.75–1.49(m,1H). 13 C NMR(CDCl 3 ,100MHz,plus,APT)δ(up)162.8,150.5,146.6,137.1,125.1,101.6,45.4,31.4,25.5；δ(down)127.9,126.5,108.5,103.9,59.7,39.2,35.8.
g. Under the protection of inert gas, adding the catalytic intermediate product (0.2 mmol,50 mg) prepared in the step f into a 10mL round-bottom flask, adding 3mL of ethanol for dissolution, then adding platinum dioxide (5% mmol,2.2 mg), finally introducing a hydrogen balloon into the reaction system, stirring at room temperature, and reacting the raw materials completely after 12 h;
the four-membered ring product was then concentrated after direct filtration as a white solid in 90% yield.
R f ＝0.29(EtOAc/PE＝1/1)； 1 H NMR(CDCl 3 ,400MHz)δ7.44(s,1H),6.65(s,1H),5.97(s,2H),4.13(dd,J＝11.7,7.5Hz,1H),3.47(dd,J＝12.8,9.0Hz,1H),3.25(td,J＝11.7,5.6Hz,1H),2.67(td,J＝12.4,5.0Hz,1H),2.53–2.39(m,1H),2.19–2.07(m,1H),2.05–1.94(m,1H),1.87–1.70(m,2H),1.72–1.60(m,3H),1.39–1.22(m,1H). 13 C NMR(CDCl 3 ,100MHz,plus,APT)δ(up)163.2,150.3,146.2,138.4,125.6,101.5,45.7,30.8,25.6,23.3,20.9；δ(down)108.5,103.9,61.0,37.4,37.2；IR(film)3516,2870,1646,1458cm -1 ；HRMS(FTMS-ESI)m/z[M+Na] + calcd for C 16 H 17 NO 3 Na 294.1101,found 294.1100.
h. Under the protection of inert gas, the four-ring product (0.17 mmol,46 mg) prepared in the step g is added into a 10mL round bottom flask, 1mL tetrahydrofuran is added for dissolution, and LiAlH is slowly added under the ice bath condition 4 (0.85 mmol,32 mg) and stirring at 60℃when the system has returned to room temperature;
TLC tracking and monitoring reaction is carried out for 5 hours, and the raw materials are completely reacted;
when the system is restored to room temperature, slowly dripping water into the system under ice bath for quenching, alternately adding water and 2M NaOH into the system when the water adding quenching is not severe, filtering, washing the organic phase with saturated salt water and anhydrous Na 2 SO 4 Drying, filtering and concentrating, and then directly carrying out rapid column chromatography separation to obtain the target product alpha-Lycorane which is white solid with the yield of 80%.
Rf＝0.24(EtOAc＝1)； 1 H NMR(CDCl 3 ,400MHz)δ6.70(s,1H),6.59(s,1H),5.89(s,2H),4.10(d,J＝15.1Hz,1H),3.77(d,J＝15.1Hz,1H),3.17–3.06(m,1H),2.82(td,J＝9.4,3.4Hz,1H),2.46–2.31(m,3H),2.26–2.18(m,1H),1.95–1.53(m,6H),1.26–1.06(m,1H). 13 C NMR(CDCl 3 ,100MHz,plus,APT)δ(up)146.1,145.4,135.1,129.0,100.7,54.7,54.2,28.0,26.2,24.9,21.0；δ(down)107.0,104.5,64.5,37.0,34.0.
Finally, it should be noted that: the foregoing description is only illustrative of the preferred embodiments of the present invention, and although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that modifications may be made to the embodiments described, or equivalents may be substituted for elements thereof, and any modifications, equivalents, improvements or changes may be made without departing from the spirit and principles of the present invention.
Claims (6)
1. The total synthesis preparation method of lycorine (+ -) -alpha-lycorane is characterized by comprising the following steps:
step a, 3,4- (methylenedioxy) cinnamic acid and 3, 5-hexadien-1-ol are used as raw materials to react to generate 3, 5-diene-1-hydroxybenzo-1, 3-dioxol-5-yl acrylate;
step b, taking 3, 5-diene-1-hydroxybenzo-1, 3-dioxole-5-yl acrylate as a raw material, and carrying out intramolecular Diels-Alder reaction to generate a lactone compound, wherein the method is concretely implemented as follows: under the protection of inert gas, sequentially adding baked 4A molecular sieve, 3, 5-diene-1-hydroxybenzo-1, 3-dioxole-5-yl acrylate and anhydrous toluene solution into a reaction container, and fully dissolving; adding diethyl aluminum chloride into the system at 0 ℃, heating to generate intramolecular Diels-Alder reaction, and collecting lactone compounds;
step c, performing bromoring opening on the lactone compound to generate a bromocompound, wherein the method is implemented as follows: under the protection of inert gas, adding a lactone compound into a reaction container; dissolving a lactone compound with dichloromethane; adding propargyl alcohol at room temperature; adding trimethyl bromosilane at 0 ℃; reacting to generate a brominated compound, and collecting;
step d, performing an azide reaction on the brominated compound to generate an azide intermediate product;
step e, performing a propargyl removal reaction on the azide intermediate product to generate an omega-azidocarboxylic acid compound, wherein the specific implementation steps are as follows: under the protection of inert gas, palladium acetate, 1, 4-bis (diphenylphosphine) butane and acetonitrile are added into a reaction container; heating to 80 ℃, stirring until the solution is clear, and then cooling to room temperature; adding triethylamine and an azidation intermediate product, and reacting at 30 ℃; the omega-azido carboxylic acid compound is generated after the reaction and then collected;
f, activating omega-azido carboxylic acid compound in situ by oxalyl chloride, and catalyzing by boron trifluoride diethyl ether to obtain a catalysis intermediate product;
step g, catalyzing the intermediate product to carry out a schmidt rearrangement reaction to generate a four-ring product;
and h, performing hydrogenation and carbonyl reduction reaction on the four-ring product to complete the total synthesis of (+ -) -alpha-lycorane.
2. The method for preparing lycorine (±) - α -lycorane by total synthesis according to claim 1, which is characterized in that: the step a comprises the following steps:
under the protection of inert gas, dissolving 3,4- (methylenedioxy) cinnamic acid and dichloromethane in a reaction vessel;
sequentially adding N, N' -dicyclohexylcarbodiimide, 4-dimethylaminopyridine and 3, 5-hexadien-1-ol;
the reaction is carried out to generate 3, 5-diene-1-hydroxybenzo-1, 3-dioxacyclopentene-5-yl acrylic ester, and then the acrylic ester is collected.
3. The method for preparing lycorine (±) - α -lycorane by total synthesis according to claim 1, which is characterized in that: the step d comprises the following steps:
dissolving a bromo compound in N, N-dimethylformamide;
adding sodium azide, and then heating to an external oil bath of 40 ℃ for reaction;
the reaction is carried out to generate an azide intermediate product, and the azide intermediate product is collected.
4. The method for preparing lycorine (±) - α -lycorane by total synthesis according to claim 1, which is characterized in that: the step f comprises the following steps:
under the protection of inert gas, adding omega-azido carboxylic acid compound and methylene dichloride into a reaction container, and dissolving;
after oxalyl chloride is added under the room temperature condition, the temperature is raised to 30 ℃ to prepare the acyl chloride in situ;
adding boron trifluoride diethyl etherate under ice bath condition, and heating to 40 ℃ for reaction;
the reaction is carried out to generate a catalytic intermediate product, and then the catalytic intermediate product is collected.
5. The method for preparing lycorine (±) - α -lycorane by total synthesis according to claim 1, which is characterized in that: the step g comprises the following steps:
under the protection of inert gas, adding a catalytic intermediate product into a reaction container, and dissolving the catalytic intermediate product with ethanol;
then adding platinum dioxide and introducing hydrogen into the reaction system;
the four-membered ring product is generated after the reaction and then collected.
6. The method for preparing lycorine (±) - α -lycorane by total synthesis according to claim 1, which is characterized in that: the step h comprises the following steps:
under the protection of inert gas, adding a four-ring product into a reaction container;
dissolving with tetrahydrofuran, and adding lithium aluminum hydride under ice bath condition;
after the system is restored to room temperature, the temperature is raised to 60 ℃ to react to generate (+ -) -alpha-lycorane, and the (+ -) -alpha-lycorane is collected.
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| "A New and Stereoselective Synthetic Route to an Amaryllidaceae Alkaloid，（±）-Lycorine";Osamu HOSHINO et al;The Chemical Society of Japan;第1365-1368页 * |
| "Palladium-Catalyzed Stereoselective Aza-Wacker−Heck Cyclization: One-Pot Stepwise Strategy toward Tetracyclic Fused Heterocycles";Rong-Shiow Tang et al;Organic Letters;第第22卷卷;第 9337−9341页 * |
| "Schmidt Reaction of ω‑Azido Valeryl Chlorides Followed by Intermolecular Trapping of the Rearrangement Ions: Synthesis of Assoanine and Related Pyrrolophenanthridine Alkaloids";Shao-Lei Ding et al;The Journal of Organic Chemistry;第第84卷卷;第 2012−2021页 * |
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