CN108864123A - A kind of synthetic method of Stemona alkaloids - Google Patents

A kind of synthetic method of Stemona alkaloids Download PDF

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CN108864123A
CN108864123A CN201810754445.7A CN201810754445A CN108864123A CN 108864123 A CN108864123 A CN 108864123A CN 201810754445 A CN201810754445 A CN 201810754445A CN 108864123 A CN108864123 A CN 108864123A
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furans
pyrrolidines
base
azatropylidene
pyrroles
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CN108864123B (en
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马开庆
任虎斌
吴晓晓
张丽增
秦雪梅
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Shanxi University
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    • 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
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
    • 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

Abstract

The invention discloses a kind of synthetic methods of Stemona alkaloids, belong to chemosynthesis technical field.The method is characterized in that： （-10℃-0℃）Under, by boron trifluoride ether (3:1 molar equivalent ratio) be added to (R,E)-methyl -4- hydroxyl -7- (1HPyrroles -1- base) heptyl -2- e pioic acid methyl ester dichloroethane solution in, reaction mixture is raised to room temperature and stirs（12-36 hours）.Obtain (3aR,10bR) -3a, 4,5,6- tetrahydro -1HFurans [3,2-c] pyrrolidines [1,2-a] azatropylidene -2 (10bH) -one.The present invention provides a kind of synthetic strategies for efficiently synthesizing Stemona alkaloids parvistemonine, lay a good foundation for the further pharmacological activity and chemical biology research of the natural products.

Description

A kind of synthetic method of Stemona alkaloids
Technical field
The present invention relates to a kind of synthetic methods of Stemona alkaloids, and in particular to a kind of natural products parvistemonine Synthetic method, belong to technical field of organic synthesis.
Background technique
Alkaloid is a kind of important natural organic-compound, and structure is complicated for they, many kinds of, and is often had very Apparent physiological activity.For thousands of years, alkaloid plays the role of in terms for the treatment of and preventing disease very outstanding as drug. Meanwhile alkaloid also plays important role in terms of plant protection.It is sub- that Stemonaceae plant belongs to Monocotyledonae lily Guiding principle pandanales, the section include 4 about 25 to 35 kinds of plants of category, mostly herbaceos perennial, there is tuberous root or blocky stem.The tuber of stemona Section plant is distributed widely in East Asia, and Southeast Asia and Australia are northern.The various plants of Stemonaceae are all important drug, in medicine Learn ancient books and records《Hundred sketches warp》,《Mingyi Bielu》In have description.The tuber of stemona class medicinal material of China is mainly from the tuber of stemona, radix stemonae sessilifoliae, With the root tuber of the big tuber of stemona.These drugs are for oral administration to be chiefly used in treating various infection, including the infection of the upper respiratory tract and parasitic infection, Cough can be treated；Simultaneously desinsection, delousing etc. can be used for external application.Why Stemonaceae plant has bioactivity so, main What is worked is Stemona aikaloids therein.Zhao Yongxing professor isolated natural products from radix stemonae tuberosae in 2016 Parvistemonine, since its structure is complicated, currently without fully synthetic report.Since the natural content of this kind of compound is few, Limit the system research and extensive utilization to its bioactivity.So the present invention to natural products parvistemonine into Row study on the synthesis, has a very important significance.
Summary of the invention
The present invention is intended to provide a kind of synthetic method of Stemona alkaloids, specially natural products parvistemonine's Synthetic method.
The present invention provides a kind of synthetic methods of Stemona alkaloids, include the following steps：2,5- dimethoxy tetrahydro furan It mutters and reacts to obtain 4- (1H- pyrrole radicals) ethyl butyrate with 4- amino fourth ethyl ester, 4- (1H- pyrroles) ethyl butyrate and methyl methoxy base Amine hydrochlorate, the reaction of isopropyl Grignard Reagent generate N- methoxy-. N-methyl -4- (1H- pyrroles -1- base) butyramide, N- methoxy Base-N- methyl -4- (1H- pyrrole radicals -1- base) butyramide reacted with vinyl Grignard Reagent generate 6- (1H- pyrroles -1- base) oneself Base -1- alkene -3- ketone, 6- (1H- pyrroles -1- base) hexyl -1- alkene -3- ketone generate 6- under the action of sodium borohydride and cerous chloride (1H- pyrroles -1- base) hexyl -1- alkene -3- alcohol, 6- (1H- pyrroles -1- base) hexyl -1- alkene -3- alcohol are catalyzed in Grubbs (two generations) Under agent effect, generation (E)-methyl -4- hydroxyl -7- (1H- pyrroles -1- base) heptyl -2- e pioic acid methyl ester is reacted with methyl acrylate, (E)-methyl -4- hydroxyl -7- (1H- pyrroles -1- base) heptyl -2- e pioic acid methyl ester generated under the catalysis of boron trifluoride ether (3a, 10b) -3a, 4,5,6- tetrahydro -1H- furans [3,2-c] pyrrolidines [1,2-a] azatropylidene -2 (10bH) -one, (3a, 10b) -3a, 4,5,6- tetrahydro -1H- furans [3,2-c] pyrrolidines [1,2-a] (10bH) -one of azatropylidene -2 is in oxalyl chloride and dimethylformamide Under the action of generate (3aR, 10bR) -2- oxygen -1,3a, 4,5,6,10b- hexahydro -2H- furans [3,2-c] pyrrolidines [1,2-a] nitrogen Miscellaneous Zhuo -8- formaldehyde, (3aR, 10bR) -2- oxygen -1,3a, 4,5,6,10b- hexahydro -2H- furans [3,2-c] pyrrolidines [1,2-a] nitrogen Miscellaneous Zhuo -8- formaldehyde reacts generation with 1- phenyl -5- (the third sulfonyl) -1H-TETRAZOLE under the action of potassium hexamethyldisilazide (3aR, 10bR) -8- ((E)-butyl -1- alkene -1- base) -1,3a, 4,5,6,10b- hexahydro -2H- furans [3,2-c] pyrrolidines [1, 2-a] azatropylidene -2- ketone, (3aR, 10bR) -8- ((E)-butyl -1- alkene -1- base) -1,3a, 4,5,6,10b- hexahydro -2H- furans [3,2-c] pyrrolidines [1,2-a] azatropylidene -2- ketone generates (3aR, 10bR) -8- butyl -1,3a under palladium carbon and hydrogen effect, 4,5,6,10b- hexahydro -2H- furans [3,2-c] pyrrolidines [1,2-a] azatropylidene -2- ketone, (3aR, 10bR) -8- butyl -1,3a, 4,5,6,10b- hexahydro -2H- furans [3,2-c] pyrrolidines [1,2-a] azatropylidene -2- ketone is in potassium hexamethyldisilazide and iodine Action-reaction generation (1R, 3aR, 10bR) -8- butyl -1- methyl-1 of methane, 3a, 4,5,6,10b-hexahydro -2H- furans [3, 2-c] pyrrolidines [1,2-a] azatropylidene -2- ketone, (1R, 3aR, 10bR) -8- butyl -1- methyl-1,3a, 4,5,6,10b-hexahydros - Epimerization occurs under potassium carbonate effect and generates natural produce for 2H- furans [3,2-c] pyrrolidines [1,2-a] azatropylidene -2- ketone Object parvistemonine.
The above method is expressed as follows with equation：
In the above method, details are as follows respectively for each step：
(1) process for preparing 4- (1H- pyrrole radicals) ethyl butyrate (6) is as follows：
2,5- dimethoxy-tetrahydrofuran is added to the water, is stirred at reflux under the conditions of argon gas.Mixture is cooled to room temperature, Methylene chloride, sodium acetate and 4-Aminobutanoicacid carbethoxy hydrochloride are added, then mixture, which is protected from light, is vigorously stirred.Sodium carbonate is added Solution, methylene chloride extraction.With magnesium sulfate drying, filtering, filtrate concentration gained residue is through column chromatography (petroleum ether：Acetic acid second Ester=1:1) azole derivatives are obtained.
(2) process for preparing N- methoxy-. N-methyl -4- (1H- pyrroles -1- base) butyramide (7) is as follows：
At -20 DEG C, the tetrahydrofuran solution of i-PrMgCl is added dropwise to 4- (1H- pyrrole radicals) ethyl butyrate (6) and Me (MeO) in the solution of NHHCl, anhydrous THF.Mixture is slowly warming up to 0 DEG C, is stirred at 0 DEG C, then with saturation chlorination Ammonium salt solution is quenched.Mixture is extracted with EA.Organic layer is merged, with anhydrous magnesium sulfate drying, filtering, filtrate concentration gained is remaining Object is through column chromatography (n-hexane：Ethyl acetate=1:1) N- methoxy-. N-methyl -4- (1H- pyrroles -1- base) butyramide is obtained.
(3) process for preparing 6- (1H- pyrroles -1- base) hexyl -1- alkene -3- ketone (8) is as follows：
At -20 DEG C, into the tetrahydrofuran solution of N- methoxy-. N-methyl -4- (1H- pyrroles -1- base) butyramide at 20 points Vinylimidazolium chloride magnesium is added dropwise in clock, reaction mixture stirs at this temperature.Under protection of argon gas, the water at -10 DEG C It is quenched.The organic layer merged, anhydrous sodium sulfate drying are washed with ether aqueous layer extracted, saturated sodium chloride solution, is concentrated under reduced pressure Crude product is directly used in next reaction.
(4) process for preparing 6- (1H- pyrroles -1- base) hexyl -1- alkene -3- alcohol (9) is as follows：
At 0 DEG C, sodium borohydride is added in the methanol of seven water cerous chlorides, which is cooled to -78 DEG C, and is added dropwise The methanol solution of 6- (1H- pyrroles -1- base) hexyl -1- alkene -3- ketone.Reaction solution is stirred at -78 DEG C, and it is water-soluble that saturated ammonium chloride is added Simultaneously removal methanol is concentrated in liquid quenching reaction.Water phase is extracted with ethyl acetate and combined organic layer, anhydrous sodium sulfate are dry, mistake Filter, filtrate concentration gained residue is through column chromatography (n-hexane：Ethyl acetate=1:1) 6- (1H- pyrroles -1- base) hexyl-is obtained 1- alkene -3- alcohol.
(5) process of (R, E)-methyl -4- hydroxyl -7- (1H- pyrroles -1- base) heptyl -2- e pioic acid methyl ester (2) is prepared such as Under：
(R) -6- (1H- pyrroles -1- base) hexyl -1- alkene -3- alcohol (0.264g, 1.6mmol) is dissolved in methylene chloride, room temperature condition In bis- generation of lower addition Grubbes catalyst and methacrylate.Reaction mixture is increased to 40 DEG C, is stirred 24 hours.It will Reaction mixture is concentrated to get residue, through column chromatography (n-hexane：Ethyl acetate=4:1) (R, E)-methyl -4- hydroxyl-is obtained 7- (1H- pyrroles -1- base) heptyl -2- e pioic acid methyl ester.
(6) (3aR, 10bR) -3a, 4,5,6- tetrahydro -1H- furans [3,2-c] pyrrolidines [1,2-a] azatropylidene -2 is prepared The process of (10bH) -one (3) is as follows：
At 0 DEG C, boron trifluoride ether is added to (R, E)-methyl -4- hydroxyl -7- (1H- pyrroles -1- base) heptyl -2- olefin(e) acid In the dichloroethane solution of methyl esters, reaction mixture is raised to room temperature and is stirred overnight.Reaction mixture is quenched with triethylamine, is stirred It mixes, organic layer is washed with water, and anhydrous sodium sulfate dries, filters, and filtrate concentration gained residue is through column chromatography (n-hexane：Acetic acid Ethyl ester=4:1) (3aR, 10bR) -3a, 4,5,6- tetrahydro -1H- furans [3,2-c] pyrrolidines [1,2-a] azatropylidene -2 is obtained (10bH) -one.Reaction equation is：
(7) (3aR, 10bR) -2- oxygen -1,3a, 4,5,6,10b- hexahydro -2H- furans [3,2-c] pyrrolidines [1,2- are prepared A] azatropylidene -8- formaldehyde (10) process it is as follows：
Under -10 DEG C, argon gas protective condition, oxalyl chloride solution is slowly dropped in dry DMF solution, generates white crystal Afterwards, it is stirred at room temperature 15 minutes, methylene chloride is then added.By (3aR, 10bR) -3a, 4,5,6- tetrahydro -1H- furans [3, 2-c] pyrrolidines [1,2-a] azatropylidene -2 (10bH) -one is slowly dropped in reaction mixture after being dissolved in methylene chloride, at room temperature Sodium acetate solution is added after stirring, continues to be stirred at room temperature.Reaction mixture is extracted with dichloromethane, uses saturated sodium chloride solution The combined organic layer of washing, anhydrous sodium sulfate dry, filter, and filtrate concentration gained residue is through column chromatography (n-hexane：Acetic acid second Ester=2:1) (3aR, 10bR) -2- oxygen -1,3a, 4,5,6,10b- hexahydro -2H- furans [3,2-c] pyrrolidines [1,2-a] nitrogen is obtained Miscellaneous Zhuo -8- formaldehyde.
(8) (3aR, 10bR) -8- ((E)-butyl -1- alkene -1- base) -1,3a, 4,5,6,10b- hexahydro -2H- furans are prepared The process of [3,2-c] pyrrolidines [1,2-a] azatropylidene -2- ketone (12) is as follows：
Under the protection of argon gas, by (3aR, 10bR) -2- oxygen -1,3a, 4,5,6,10b- hexahydro -2H- furans [3,2-c] pyrroles Alkane [1,2-a] azatropylidene -8- formaldehyde and 1- phenyl -5- (the third sulfonyl) -1H-TETRAZOLE are dissolved in dry tetrahydrofuran, then cold But to -78 DEG C, potassium hexamethyldisilazide is slowly added dropwise at this temperature, finishes, is stirred to react at this temperature 30 minutes, Then it is warmed to room temperature reaction 12h, saturation NH is added at 0 DEG C4Cl solution is extracted with dichloromethane, with terminating reaction with saturation Sodium chloride solution washs combineds organic layer, anhydrous sodium sulfate dries, filters, residue obtained by filtrate concentration through column chromatography (just Hexane：Ethyl acetate=3:1) (3aR, 10bR) -8- ((E)-butyl -1- alkene -1- base) -1,3a, 4,5,6,10b- hexahydro-are obtained 2H- furans [3,2-c] pyrrolidines [1,2-a] azatropylidene -2- ketone.
(9) prepare (3aR, 10bR) -8- butyl -1,3a, 4,5,6,10b- hexahydro -2H- furans [3,2-c] pyrrolidines [1, 2-a] azatropylidene -2- ketone (13) process it is as follows：
By (3aR, 10bR) -8- ((E)-butyl -1- alkene -1- base) -1,3a, 4,5,6,10b- hexahydro -2H- furans [3,2-c] pyrrole It coughs up alkane [1,2-a] azatropylidene -2- ketone to be dissolved in ethyl alcohol, palladium/carbon is added, under hydrogen effect, room temperature reaction.Reaction mixture mistake Filter removes palladium/carbon in solution with diatomite, and filtrate is concentrated to get (3aR, 10bR) -8- butyl -1,3a, 4,5,6,10b- hexahydros - 2H- furans [3,2-c] pyrrolidines [1,2-a] azatropylidene -2- ketone.
(10) (1R, 3aR, 10bR) -8- butyl -1- methyl-1,3a, 4,5,6,10b-hexahydro -2H- furans [3,2- are prepared C] pyrrolidines [1,2-a] azatropylidene -2- ketone (14) process it is as follows：
Under the protection of argon gas, by (3aR, 10bR) -8- butyl -1,3a, 4,5,6,10b- hexahydro -2H- furans [3,2-c] pyrroles It coughs up alkane [1,2-a] azatropylidene -2- ketone to be dissolved in dry tetrahydrofuran, is subsequently cooled to -78 DEG C, be slowly added dropwise at this temperature double Reaction flask is moved at 0 DEG C after reacting at this temperature and is reacted, is then cooled to -78 DEG C again by (trimethyl silicon substrate) lithium amide, Iodomethane is added, the reaction was continued at this temperature；It is warmed to room temperature, saturation NH is added4Cl is extracted with terminating reaction with methylene chloride It takes, wash the organic layer merged with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, filtrate concentration gained residue warp Column chromatography (n-hexane：Ethyl acetate=3:1) (1R, 3aR, 10bR) -8- butyl -1- methyl-1,3a, 4,5,6,10b-six are obtained Hydrogen -2H- furans [3,2-c] pyrrolidines [1,2-a] azatropylidene -2- ketone.
(11) process for preparing natural products parvistemonine (1) is as follows：
By (1R, 3aR, 10bR) -8- butyl -1- methyl-1,3a, 4,5,6,10b-hexahydro -2H- furans [3,2-c] pyrrolidines [1, 2-a] azatropylidene -2- ketone is dissolved in ethyl alcohol, and potassium carbonate is added, is stirred at room temperature.Reaction mixture is extracted with dichloromethane three It is secondary, merge organic phase, filtering, filtrate concentration gained residue is through column chromatography (n-hexane：Ethyl acetate=3:1) it is naturally produced Object parvistemonine.
Beneficial effects of the present invention：The present invention provides a kind of conjunctions for efficiently synthesizing Stemona alkaloids parvistemonine At strategy, lay a good foundation for the further pharmacological activity and chemical biology research of the natural products.
Detailed description of the invention
Fig. 1 is the H spectrogram of 1 products therefrom of embodiment；
Fig. 2 is the C spectrogram of 1 products therefrom of embodiment；
Fig. 3 is the H spectrogram of 2 products therefrom of embodiment；
Fig. 4 is the C spectrogram of 2 products therefrom of embodiment；
Fig. 5 is the H spectrogram of 4 products therefrom of embodiment；
Fig. 6 is the C spectrogram of 4 products therefrom of embodiment；
Fig. 7 is the H spectrogram of 5 products therefrom of embodiment；
Fig. 8 is the C spectrogram of 5 products therefrom of embodiment；
Fig. 9 is the H spectrogram of 6 products therefrom of embodiment；
Figure 10 is the C spectrogram of 6 products therefrom of embodiment；
Figure 11 is the H spectrogram of 8 products therefrom of embodiment；
Figure 12 is the C spectrogram of 8 products therefrom of embodiment；
Figure 13 is the H spectrogram of 9 products therefrom of embodiment；
Figure 14 is the C spectrogram of 9 products therefrom of embodiment；
Figure 15 is the H spectrogram of 10 products therefrom of embodiment；
Figure 16 is the C spectrogram of 10 products therefrom of embodiment；
Figure 17 is the H spectrogram of 11 products therefrom of embodiment；
Figure 18 is the C spectrogram of 11 products therefrom of embodiment；
Figure 19 is the H spectrogram of 12 products therefrom of embodiment；
Figure 20 is the C spectrogram of 12 products therefrom of embodiment.
Specific embodiment
The present invention is further illustrated below by embodiment, but is not limited to following embodiment.
The present invention relates to the synthetic methods of natural products parvistemonine.Now in conjunction with the synthetic reaction in summary of the invention The present invention is further described for formula and embodiment.
Embodiment 1 prepares 4- (1H- pyrrole radicals) ethyl butyrate (6)
2,5- dimethoxy-tetrahydrofuran (8.5g, 63mmol) is added in water (180mL), is stirred at reflux under the conditions of argon gas 2 hours.Mixture is cooled to room temperature, methylene chloride (100mL), sodium acetate (13g, 155mmol) and 4- amino fourth are added Acid ethyl ester hydrochloride salt (13g, 78mmol), then mixture, which is protected from light, is vigorously stirred 15 hours.The sodium carbonate liquor of 2M concentration is added (20mL), methylene chloride extraction.With magnesium sulfate drying, filtering, filtrate concentration gained residue is through column chromatography (petroleum ether：Acetic acid Ethyl ester=1:1) azole derivatives 9.0g (yield is obtained：77%).
FTIR(neat,cm-1)νmax2980,1732,1500,1447,1375,1282,725；
1H NMR(500MHz,CDCl3)δ:6.64 (t, J=2.0Hz, 2H), 6.14 (t, J=2.1Hz, 2H), 4.13 (q, J= 7.1Hz, 2H), 3.94 (t, J=6.9Hz, 2H), 2.27 (t, J=7.3Hz, 2H), 2.13-2.02 (m, 2H), 1.26 (t, J= 7.1Hz,3H).
13C NMR(126MHz,CDCl3)δ:172.8,120.6,108.2,60.5,48.5,31.0,26.8,14.2；
There is the hydrogen of aryl domains in chemical shift 6.64 and 6.14 in hydrogen spectrum, illustrates the formation of pyrroles.
Embodiment 2 prepares N- methoxy-. N-methyl -4- (1H- pyrroles -1- base) butyramide (7)
At -20 DEG C, the tetrahydrofuran solution of the i-PrMgCl (0.64mL, 1.27mmol) of 2.0M concentration is added dropwise to 4- (1H- pyrrole radicals) ethyl butyrate (6) (0.1g, 0.55mmol) and Me (MeO) NHHCl (64mg, 0.66mmol) anhydrous THF In the solution of (1.5mL).Mixture is slowly warming up to 0 DEG C, stirs 2 hours at 0 DEG C, is then quenched with saturated ammonium chloride solution It goes out.Mixture is extracted with EA.Organic layer is merged, with anhydrous magnesium sulfate drying, filtering, filtrate concentration gained residue is through column color Compose (n-hexane：Ethyl acetate=1:1) N- methoxy-. N-methyl -4- (1H- pyrroles -1- base) butyramide 0.1g (yield is obtained： 92%).
FTIR(neat,cm-1)νmax29377,1660,1500,1445,1386,1281,726；
1H NMR(500MHz,CDCl3)δ:6.65 (t, J=2.1Hz, 2H), 6.13 (t, J=2.1Hz, 2H), 3.97 (t, J= 6.8Hz, 2H), 3.60 (s, 3H), 3.17 (s, 3H), 2.36 (t, J=7.1Hz, 2H), 2.06-2.12 (m, 2H)
13C NMR(126MHz,CDCl3)δ:173.6,120.6,108.0,61.1,48.7,32.2,28.4,26.2.
There are methyl singlets in chemical shift 3.60 and 3.17 in hydrogen spectrum, illustrates that Weinreb amide is formed.
Embodiment 3 prepares 6- (1H- pyrroles -1- base) hexyl -1- alkene -3- ketone (8)
At -20 DEG C, to the tetrahydro furan of N- methoxy-. N-methyl -4- (1H- pyrroles -1- base) butyramide (2.6g, 13.3mmol) It mutters and vinylimidazolium chloride magnesium (1M tetrahydrofuran solution, 16ml, 16mmol) is added dropwise in 20 minutes in (120mL) solution, instead Mixture is answered to stir at this temperature 2 hours.Under protection of argon gas, it is quenched at -10 DEG C with water (50mL).With ether extraction water Layer, saturated sodium chloride solution wash combined organic layer, anhydrous sodium sulfate drying, and crude product is concentrated under reduced pressure to obtain, it is directly used In next reaction.
Embodiment 4 prepares 6- (1H- pyrroles -1- base) hexyl -1- alkene -3- alcohol (9)
At 0 DEG C, sodium borohydride (1.6g, 44mmol) is added to the methanol (107ml) of seven water cerous chlorides (12g, 33mmol) In, which is cooled to -78 DEG C, and the methanol of 6- (1H- pyrroles -1- base) hexyl -1- alkene -3- ketone (2.6g) is added dropwise (36ml) solution.Reaction solution stirs 2 hours at -78 DEG C, and saturated aqueous ammonium chloride quenching reaction is added and removal methanol is concentrated. Water phase is extracted with ethyl acetate and combined organic layer, anhydrous sodium sulfate dry, filter, and filtrate concentration gained residue is through column color Compose (n-hexane：Ethyl acetate=1:1) 6- (1H- pyrroles -1- base) hexyl -1- alkene -3- alcohol 1.5g (yield is obtained：Two steps 65%).
FTIR(neat,cm-1)νmax 3403,3098,2942,2874,1697,1500,1369,1280.69,1090, 992,724；
1H NMR(500MHz,CDCl3)δ:6.65 (t, J=2.0Hz, 2H), 6.14 (t, J=2.1Hz, 2H), 5.84 (ddd, J =16.9,10.4,6.2Hz, 1H), 5.22 (dt, J=17.2,1.4Hz, 1H), 5.12 (dt, J=10.4,1.3Hz, 1H), 4.12-4.06 (m, 1H), 3.91 (td, J=7.1,1.2Hz, 2H), 1.95-1.76 (m, 2H), 1.55-1.50 (m, 2H)；
13C NMR(126MHz,CDCl3)δ140.7,120.4,114.9,107.8,72.5,49.3,33.8,27.3；
There is multiplet in chemical shift 4.12-4.06 in hydrogen spectrum, illustrates that carbonyl is reduced to hydroxyl.
Embodiment 5 prepares (R, E)-methyl -4- hydroxyl -7- (1H- pyrroles -1- base) heptyl -2- e pioic acid methyl ester (2)
(R) -6- (1H- pyrroles -1- base) hexyl -1- alkene -3- alcohol (0.264g, 1.6mmol) is dissolved in methylene chloride (4ml), room It is added in bis- generation of Grubbes catalyst (66mg, 0.08mmol) and methacrylate (1.37g, 16mmol) under the conditions of temperature.It will Reaction mixture is increased to 40 DEG C, stirs 24 hours.Reaction mixture is concentrated to get residue, through column chromatography (n-hexane：Second Acetoacetic ester=4:1) (R, E)-methyl -4- hydroxyl -7- (1H- pyrroles -1- base) heptyl -2- e pioic acid methyl ester 0.32g (yield is obtained： 92%).
FTIR(neat,cm-1)νmax3462,2950,1722,1660,1500,1437,1280,729；
1H NMR(500MHz,CDCl3) δ 6.89 (dd, J=15.7,4.9Hz, 1H), 6.64 (t, J=2.1Hz, 2H), 6.14 (t, J=2.1Hz, 2H), 6.01 (dd, J=15.7,1.6Hz, 1H), 4.35-4.11 (m, 1H), 3.91 (td, J=7.0, 2.1Hz,2H),3.74(s,3H),2.13(s,1H),1.99–1.76(m,2H),1.65–1.40(m,2H).
13C NMR(126MHz,CDCl3)δ166.9,150.0,120.5,120.1,108.1,70.5,51.7,49.3,33.5, 27.2；
There is the peak dd in chemical shift 6.89 in hydrogen spectrum, 3.74 appearance are unimodal, illustrate that unsaturated methyl esters is formed.
Embodiment 6 prepares (3aR, 10bR) -3a, 4,5,6- tetrahydro -1H- furans [3,2-c] pyrrolidines [1,2-a] azepine Tall and erect -2 (10bH) -one (3)
At 0 DEG C, boron trifluoride ether (0.16mL, 1.28mmol) is added to (R, E)-methyl -4- hydroxyl -7- (1H- pyrrole Cough up -1- base) (molar equivalent ratio herein is 1.2 to heptyl -2- e pioic acid methyl ester (237mg, 1.06mmol):1) dichloroethanes In 36mL solution, reaction mixture is raised to room temperature and is stirred overnight.Reaction mixture is quenched with triethylamine, stirs 30 minutes, has Machine layer is washed with water, and anhydrous sodium sulfate dries, filters, and filtrate concentration gained residue is through column chromatography (n-hexane：Ethyl acetate= 4:1) 89.4mg (yield is obtained：45%).
FTIR(neat,cm-1)νmax2937,1778,1487,1193,1137,1019,716；
1H NMR(500MHz,CDCl3)δ:6.62 (t, J=2.3Hz, 1H), 6.03 (t, J=3.3Hz, 1H), 5.94-5.95 (m, 1H), 4.10-4.14 (m, 1H), 3.97 (ddd, J=11.2,9.9,3.5Hz, 1H), 3.88 (ddd, J=14.6,11.7, 1.0Hz,1H),3.44–3.36(m,1H),2.94–2.87(m,2H),2.58–2.49(m,1H),2.10–2.15(m,1H), 1.77–1.85(m,1H),1.75–1.63(m,1H).
13C NMR(126MHz,CDCl3)δ:175.2,128.6,122.8,106.4,105.5,83.7,49.1,42.2,34.0, 33.7,26.1；
It disappears in hydrogen spectrum at 6.64 peak of chemical shift, 3.74 unimodal disappearances illustrate that lactone compound is formed.
Embodiment 7 prepares (3aR, 10bR) -3a, 4,5,6- tetrahydro -1H- furans [3,2-c] pyrrolidines [1,2-a] azepine Tall and erect -2 (10bH) -one (3)
At 0 DEG C, boron trifluoride ether (0.66mL, 5.3mmol) is added to (R, E)-methyl -4- hydroxyl -7- (1H- pyrroles - 1- yl) (molar equivalent ratio herein is 5 to heptyl -2- e pioic acid methyl ester (237mg, 1.06mmol):1) dichloroethanes 36mL solution In, reaction mixture is raised to room temperature and is stirred overnight.Reaction mixture is quenched with triethylamine, is stirred 30 minutes, organic layer water Washing, anhydrous sodium sulfate dry, filter, and filtrate concentration gained residue is through column chromatography (n-hexane：Ethyl acetate=4:1) it obtains 89.4mg (yield：21%).
Embodiment 8 prepares (3aR, 10bR) -2- oxygen -1,3a, 4,5,6,10b- hexahydro -2H- furans [3,2-c] pyrrolidines [1,2-a] azatropylidene -8- formaldehyde (10)
Under -10 DEG C, argon gas protective condition, oxalyl chloride (2.0M dichloromethane solution, 2.4mL, 4.8mmol) solution is slowly dripped It is added in dry DMF solution (0.72ml, 9.6mmol), after generating white crystal, is stirred at room temperature 15 minutes, then add Enter methylene chloride (100mL).By (3aR, 10bR) -3a, 4,5,6- tetrahydro -1H- furans [3,2-c] pyrrolidines [1,2-a] azepine Tall and erect -2 (10bH) -one (900mg, 4.7mmol) are slowly dropped in reaction mixture after being dissolved in 50mL methylene chloride, are stirred at room temperature 2.0M sodium acetate solution 20ml is added after mixing 0.5h, continues that 2h is stirred at room temperature.Reaction mixture is extracted with dichloromethane, with full Combined organic layer, anhydrous sodium sulfate dry, filter with sodium chloride solution washing, and filtrate concentration gained residue is through column chromatography (n-hexane：Ethyl acetate=2:1) (3aR, 10bR) -2- oxygen -1,3a, 4,5,6,10b- hexahydro -2H- furans [3,2-c] is obtained Pyrrolidines [1,2-a] azatropylidene -8- formaldehyde 375.4mg (yield：37%).
1H NMR(600MHz,CDCl3) δ 9.51 (s, 1H), 6.87 (d, J=4.0Hz, 1H), 6.10 (d, J=3.9Hz, 1H), 5.84 (dd, J=14.7,5.6Hz, 1H), 4.04 (td, J=10.8,3.5Hz, 1H), 3.70 (dd, J=14.5, 11.8Hz, 1H), 3.51 (dd, J=20.7,10.0Hz, 1H), 2.97 (m, 2H), 2.60 (dd, J=13.0,3.4Hz, 1H), 2.18-2.24 (m, 1H), 1.85-1.90 (ddd, J=16.0,13.2,3.5Hz, 1H), 1.70 (dd, J=26.8,13.3Hz, 1H).
13C NMR(151MHz,CDCl3)δ179.9,174.3,139.9,132.5,124.67,107.3,82.2,45.5,41.8, 34.4,33.2,25.3；
Hydrogen spectrum in occur in chemical shift 9.51 it is unimodal, illustrate generate aldehyde radical.
Embodiment 9 prepares (3aR, 10bR) -8- ((E)-butyl -1- alkene -1- base) -1,3a, 4,5,6,10b- hexahydro -2H- Furans [3,2-c] pyrrolidines [1,2-a] azatropylidene -2- ketone (12)
Under the protection of argon gas, by (3aR, 10bR) -2- oxygen -1,3a, 4,5,6,10b- hexahydro -2H- furans [3,2-c] pyrroles Alkane [1,2-a] azatropylidene -8- formaldehyde (100mg, 0.46mmol) and 1- phenyl -5- (the third sulfonyl) -1H-TETRAZOLE (150mg, It 0.59mmol) is dissolved in 15mL dry tetrahydrofuran, is subsequently cooled to -78 DEG C, two silicon of hexamethyl is slowly added dropwise at this temperature Base amido potassium (1.0M tetrahydrofuran solution, 1mL, 1mmol) finishes, and is stirred to react 30 minutes at this temperature, then rises to room Temperature reaction 12h, is added the saturation NH of 5mL at 0 DEG C4Cl solution is extracted with dichloromethane to terminate reaction, uses saturated sodium-chloride Solution washs combined organic layer, anhydrous sodium sulfate dries, filters, and filtrate concentration gained residue is through column chromatography (n-hexane：Second Acetoacetic ester=3:1) (3aR, 10bR) -8- ((E)-butyl -1- alkene -1- base) -1,3a, 4,5,6,10b- hexahydro -2H- furans are obtained [3,2-c] pyrrolidines [1,2-a] azatropylidene -2- ketone 61mg (yield：54%).
1H NMR(600MHz,CDCl3) δ 6.23 (d, J=15.6Hz, 1H), 6.15 (d, J=3.1Hz, 1H), 6.08- 5.98 (m, 1H), 5.91 (d, J=2.5Hz, 1H), 4.36 (dd, J=14.9,5.6Hz, 1H), 4.06-3.92 (m, 1H), 3.72-3.59 (m, 1H), 3.44 (dd, J=21.2,9.2Hz, 1H), 2.91 (qd, J=16.7,10.4Hz, 2H), 2.62- 2.47 (m, 1H), 2.22 (p, J=7.0Hz, 2H), 2.19-2.11 (m, 1H), 1.88-1.79 (m, 1H), 1.65-1.62 (m, 1H), 1.09 (t, J=7.4Hz, 3H)
13C NMR(151MHz,CDCl3)δ175.3,133.2,133.0,129.1,104.8,104.1,83.7,44.3,42.3, 34.2,33.5,26.3,25.8,13.7；
There is the peak t in chemical shift 1.09 in hydrogen spectrum, 6.02 the peak d occur, and 6.08-5.98 the peak d occurs, illustrates unsaturated fatty chain It is formed.
Embodiment 10 prepares (3aR, 10bR) -8- butyl -1,3a, 4,5,6,10b- hexahydro -2H- furans [3,2-c] pyrroles Alkane [1,2-a] azatropylidene -2- ketone (13)
By (3aR, 10bR) -8- ((E)-butyl -1- alkene -1- base) -1,3a, 4,5,6,10b- hexahydro -2H- furans [3,2-c] pyrrole It coughs up alkane [1,2-a] azatropylidene -2- ketone (50mg, 0.2mmol) to be dissolved in 5ml ethyl alcohol, palladium/carbon is added, under hydrogen effect, room temperature Reaction 3 hours.Reaction mixture filtering removes palladium/carbon in solution with diatomite, and filtrate is concentrated to get (3aR, 10bR) -8- fourth Base -1,3a, 4,5,6,10b- hexahydro -2H- furans [3,2-c] pyrrolidines [1,2-a] azatropylidene -2- ketone 48mg (yield：96%).
1H NMR(600MHz,CDCl3) δ 5.86 (s, 1H), 5.81 (d, J=3.0Hz, 1H), 4.21 (dd, J=14.8, 5.6Hz, 1H), 3.99 (td, J=10.8,3.3Hz, 1H), 3.79-3.55 (m, 1H), 3.42 (dd, J=21.5,9.0Hz, 1H), 2.91 (ddd, J=24.4,16.7,10.4Hz, 2H), 2.63-2.45 (m, 3H), 2.27-2.09 (m, 1H), 1.84 (ddd, J=15.8,13.5,3.2Hz, 1H), 1.72-1.48 (m, 3H), 1.41 (dq, J=14.7,7.3Hz, 2H), 0.96 (t, J=7.3Hz, 3H)
13C NMR(151MHz,CDCl3)δ175.5,134.5,128.1,104.3,103.4,83.9,44.2,42.4,34.3, 33.6,31.6,26.3,26.0,22.5,13.9；
In the bimodal disappearance of chemical shift 6.02 in hydrogen spectrum, the peak 6.08-5.98 disappears, and illustrates that double bond disappears.
Embodiment 11 prepares (1R, 3aR, 10bR) -8- butyl -1- methyl-1,3a, 4,5,6,10b-hexahydro -2H- furans [3,2-c] pyrrolidines [1,2-a] azatropylidene -2- ketone (14)
Under the protection of argon gas, by (3aR, 10bR) -8- butyl -1,3a, 4,5,6,10b- hexahydro -2H- furans [3,2-c] pyrroles It coughs up alkane [1,2-a] azatropylidene -2- ketone to be dissolved in 2.7mL dry tetrahydrofuran, is subsequently cooled to -78 DEG C, at this temperature slowly Bis- (trimethyl silicon substrate) lithium amides (1.0M tetrahydrofuran solution, 0.24mL, 0.24mmol) are added dropwise, react 10 points at this temperature Reaction flask is moved at 0 DEG C after clock and is reacted 5 minutes, is then cooled to -78 DEG C again, be added iodomethane (0.26mL, 0.26mmol), the reaction was continued at this temperature 3h.It is warmed to room temperature, saturation NH is added4Cl is extracted with terminating reaction with methylene chloride It takes, wash the organic layer merged with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, filtrate concentration gained residue warp Column chromatography (n-hexane：Ethyl acetate=3:1) (1R, 3aR, 10bR) -8- butyl -1- methyl-1,3a, 4,5,6,10b-six are obtained Hydrogen -2H- furans [3,2-c] pyrrolidines [1,2-a] azatropylidene -2- ketone 27mg (yield：64%).
1H NMR(600MHz,CDCl3) δ 6.06 (d, J=3.5Hz, 1H), 5.83 (d, J=3.5Hz, 1H), 4.34 (td, J =10.7,4.0Hz, 1H), 4.23 (dd, J=14.8,6.0Hz, 1H), 3.55 (dd, J=14.7,11.4Hz, 1H), 3.43 (dd, J=10.2,7.1Hz, 1H), 3.13 (p, J=7.3Hz, 1H), 2.64-2.58 (m, 1H), 2.54 (t, J=7.8Hz, 2H), 2.18-2.10 (m, 1H), 1.77 (ddd, J=16.1,13.3,3.3Hz, 1H), 1.69-1.60 (m, 1H), 1.61-1.54 (m, 5H), 1.46-1.37 (m, 2H), 0.96 (t, J=7.3Hz, 3H)
13C NMR(151MHz,CDCl3)δ179.2,134.1,125.7,105.7,104.6,80.9,45.6,44.9,39.7, 34.9,31.5,26.5,25.4,22.6,13.9,12.6；
There is methyl peak at the peak chemical shift 1.61-1.54 in hydrogen spectrum, illustrates to form methyl.
Embodiment 12 prepares natural products parvistemonine (1)
By (1R, 3aR, 10bR) -8- butyl -1- methyl-1,3a, 4,5,6,10b-hexahydro -2H- furans [3,2-c] pyrrolidines [1, 2-a] azatropylidene -2- ketone (6mg, 0.023mmol) is dissolved in 0.5ml ethyl alcohol, it is added potassium carbonate (5mg, 0.035mmol), in room Temperature is lower to stir 12h.Reaction mixture is extracted with dichloromethane three times, merges organic phase, filtering, filtrate concentration gained residue warp Column chromatography (n-hexane：Ethyl acetate=3:1) natural products parvistemonine 3mg (yield is obtained：50%).
1H NMR(600MHz,CDCl3) δ 5.88 (d, J=3.2Hz, 1H), 5.84 (d, J=3.4Hz, 1H), 4.21 (dd, J =14.8,5.6Hz, 1H), 3.97-3.82 (m, 1H), 3.65 (dd, J=14.7,11.7Hz, 1H), 3.00 (tt, J=13.2, 9.6Hz, 2H), 2.61-2.48 (m, 3H), 2.20-2.09 (m, 1H), 1.79 (ddd, J=24.6,13.1,3.5Hz, 1H), 1.66-1.51 (m, 4H), 1.42 (dd, J=17.2,7.0Hz, 4H), 0.97 (t, J=7.4Hz, 3H)；
13C NMR(151MHz,CDCl3)δ178.5,134.3,128.1,104.3,103.0,81.8,49.4,44.2,39.4, 34.4,31.6,26.3,26.0,22.5,13.9,13.9；
Hydrogen spectrum and carbon spectrum are consistent with natural products.

Claims (6)

1. a kind of synthetic method of Stemona alkaloids, it is characterised in that：Include the following steps：2,5- dimethoxy-tetrahydrofuran It reacts to obtain 4- (1 with 4- amino fourth ethyl esterHPyrrole radicals) ethyl butyrate, 4- (1HPyrroles) ethyl butyrate and methyl methoxy base Amine hydrochlorate, the reaction of isopropyl Grignard Reagent generateNMethoxyl group-NMethyl -4- (1HPyrroles -1- base) butyramide,NMethoxy Base-NMethyl -4- (1HPyrrole radicals -1- base) butyramide reacted with vinyl Grignard Reagent generate 6- (1HPyrroles -1- base) oneself Base -1- alkene -3- ketone, 6- (1HPyrroles -1- base) hexyl -1- alkene -3- ketone generates 6- under the action of sodium borohydride and cerous chloride (1HPyrroles -1- base) hexyl -1- alkene -3- alcohol, 6- (1HPyrroles -1- base) hexyl -1- alkene -3- alcohol Grubbs (two generations) be catalyzed Agent effect under, reacted with methyl acrylate generation (E)-methyl -4- hydroxyl -7- (1HPyrroles -1- base) heptyl -2- e pioic acid methyl ester, (E)-methyl -4- hydroxyl -7- (1HPyrroles -1- base) heptyl -2- e pioic acid methyl ester generates under the catalysis of boron trifluoride ether (3aR, 10b) and -3a, 4,5,6- tetrahydro -1HFurans [3,2-c] pyrrolidines [1,2-a] azatropylidene -2 (10bH) -one, (3aR, 10b) and -3a, 4,5,6- tetrahydro -1HFurans [3,2-c] pyrrolidines [1,2-a] azatropylidene -2 (10bH) -one exists (3a is generated under the action of oxalyl chloride and dimethylformamideR, 10bR) -2- oxygen -1,3a, 4,5,6,10b- hexahydro -2H- Furans [3,2-c] pyrrolidines [1,2-a] azatropylidene -8- formaldehyde, (3aR, 10bR) -2- oxygen -1,3a, 4,5,6,10b- six Hydrogen -2HFurans [3,2-c] pyrrolidines [1,2-a] azatropylidene -8- formaldehyde and 1- phenyl -5- (the third sulfonyl) -1HTetrazolium is six Reaction generates (3a under the action of two silicon substrate amido potassium of methylR,10bR)-8-((E)-butyl -1- alkene -1- base) -1,3a, 4, 5,6,10b- hexahydro -2HFurans [3,2-c] pyrrolidines [1,2-a] azatropylidene -2- ketone, (3aR,10bR)-8-((E)-fourth Base -1- alkene -1- base) -1,3a, 4,5,6,10b- hexahydro -2HFurans [3,2-c] pyrrolidines [1,2-a] azatropylidene -2- Ketone generates (3a under palladium carbon and hydrogen effectR,10bR) -8- butyl -1,3a, 4,5,6,10b- hexahydro -2HFurans [3, 2-c] pyrrolidines [1,2-a] azatropylidene -2- ketone, (3aR,10bR) -8- butyl -1,3a, 4,5,6,10b- hexahydro -2H- Furans [3,2-c] pyrrolidines [1,2-a] azatropylidene -2- ketone is raw in the action-reaction of potassium hexamethyldisilazide and iodomethane At (1R, 3aR, 10bR) -8- butyl -1- methyl-1,3a, 4,5,6,10b-hexahydro -2HFurans [3,2-c] pyrroles Alkane [1,2-a] azatropylidene -2- ketone, (1R, 3aR, 10bR) -8- butyl -1- methyl-1,3a, 4,5,6,10b-hexahydro - 2HFurans [3,2-c] pyrrolidines [1,2-a] azatropylidene -2- ketone occurs epimerization under potassium carbonate effect and generates naturally Product parvistemonine；The structural formula of gained natural products parvistemonine is：
。
2. the synthetic method of Stemona alkaloids according to claim 1, it is characterised in that：(E)-methyl -4- hydroxyl -7- (1HPyrroles -1- base) heptyl -2- e pioic acid methyl ester prepares (3a, 10b) -3a, 4,5,6- tetrahydro -1HFurans [3,2-c] pyrrole Cough up alkane [1,2-a] azatropylidene -2 (10bH) process of -one is：At -10 DEG C ~ 0 DEG C, boron trifluoride ether is added to (R,E)-methyl -4- hydroxyl -7- (1HPyrroles -1- base) heptyl -2- e pioic acid methyl ester dichloroethane solution in, the molar equivalent of the two Than being 1:1 ~ 5:1, reaction mixture is raised to room temperature and stirs 12-36 hours, obtains (3aR, 10bR)-3a, 4, 5, 6- Tetrahydro -1HFurans [3,2-c] pyrrolidines [1,2-a] azatropylidene -2 (10bH) -one.
3. the synthetic method of Stemona alkaloids according to claim 2, it is characterised in that：At 0 DEG C, by boron trifluoride Ether be added to 36 mL (R, E)-methyl -4- hydroxyl -7- (1HPyrroles -1- base) heptyl -2- e pioic acid methyl ester dichloroethanes it is molten In liquid, boron trifluoride ether with (R, E)-methyl -4- hydroxyl -7- (1HPyrroles -1- base) heptyl -2- e pioic acid methyl ester molar ratio It is 1.2:1, reaction mixture is raised to room temperature and is stirred overnight；Reaction mixture is quenched with triethylamine, is stirred 30 minutes, organic Layer is washed with water, and anhydrous sodium sulfate dries, filters, and filtrate concentration, gained residue is through column chromatography：N-hexane：Ethyl acetate= 4:1 detection, obtains product (3aR, 10bR) -3a, 4,5,6- tetrahydro -1HFurans [3,2-c] pyrrolidines [1,2-a] nitrogen - 2 (10b of miscellaneous ZhuoH) 89.4 mg of -one, yield 45%.
4. the synthetic method of Stemona alkaloids according to claim 1, it is characterised in that：Prepare (3aR,10bR)-8- ((E)-butyl -1- alkene -1- base) -1,3a, 4,5,6,10b- hexahydro -2HFurans [3,2-c] pyrrolidines [1,2-a] nitrogen Miscellaneous Zhuo -2- ketone（12）Process it is as follows：Under the protection of argon gas, by (3aR, 10bR) -2- oxygen -1,3a, 4,5,6, 10b- hexahydro -2HFurans [3,2-c] pyrrolidines [1,2-a] azatropylidene -8- formaldehyde and 1- phenyl -5- (the third sulfonyl) -1H- four Azoles, the molar equivalent ratio of the two are 1:1.1 ~ 1:5, it is dissolved in dry tetrahydrofuran, is subsequently cooled to -78 DEG C, it is warm herein Potassium hexamethyldisilazide, potassium hexamethyldisilazide and (3aR, 10bR) -2- oxygen -1,3a are slowly added dropwise under degree, The ratio of 4,5,6,10b- hexahydro -2H- furans [3,2-c] pyrrolidines [1,2-a] azatropylidene -8- formaldehyde is 1:2~1:5, add Finish, be stirred to react at this temperature 30 minutes, be then warmed to room temperature 12 h of reaction, saturation NH is added at 0 DEG C4Cl Solution is extracted with dichloromethane to terminate reaction, the organic layer merged is washed with saturated sodium chloride solution, anhydrous sodium sulfate is done Dry, filtering, filtrate concentration gained residue is through column chromatography：N-hexane：Ethyl acetate=3:1, obtain (3aR,10bR)-8- ((E)-butyl -1- alkene -1- base) -1,3a, 4,5,6,10b- hexahydro -2HFurans [3,2-c] pyrrolidines [1,2-a] nitrogen Miscellaneous Zhuo -2- ketone.
5. the synthetic method of Stemona alkaloids according to claim 4, it is characterised in that：Under the protection of argon gas, will (3aR, 10bR) -2- oxygen -1,3a, 4,5,6,10b- hexahydro -2HFurans [3,2-c] pyrrolidines [1,2-a] azatropylidene- 8- formaldehyde and 1- phenyl -5- (the third sulfonyl) -1HTetrazolium is dissolved in 15 mL dry tetrahydrofurans, wherein (3aR, 10bR)- 2- oxygen -1,3a, 4,5,6,10b- hexahydro -2HFurans [3,2-c] pyrrolidines [1,2-a] azatropylidene -8- formaldehyde and 1- benzene Base -5- (the third sulfonyl) -1HThe molar ratio of tetrazolium is：1 : 1.3；- 78 DEG C are subsequently cooled to, is slowly added dropwise at this temperature Potassium hexamethyldisilazide, potassium hexamethyldisilazide and (3aR, 10bR) -2- oxygen -1,3a, 4,5,6,10b- The ratio of hexahydro -2H- furans [3,2-c] pyrrolidines [1,2-a] azatropylidene -8- formaldehyde is 1:2.2, it finishes, at this temperature It is stirred to react 30 minutes, is then warmed to room temperature 12 h of reaction, 5 mL saturation NH is added at 0 DEG C4Cl solution is with end It only reacts, is extracted with dichloromethane, washs the organic layer merged with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, filter Liquid concentration gained residue is through column chromatography：N-hexane：Ethyl acetate=3:1, obtain (3aR,10bR)-8-((E)-butyl -1- Alkene -1- base) -1,3a, 4,5,6,10b- hexahydro -2HFurans [3,2-c] pyrrolidines [1,2-a] azatropylidene -2- ketone 61 Mg, yield 54%.
6. the synthetic method of Stemona alkaloids according to claim 1, it is characterised in that：Include the following steps：
（1）Prepare 4- (1HPyrrole radicals) ethyl butyrate process it is as follows：
2,5- dimethoxy-tetrahydrofuran is added to the water, is stirred at reflux under the conditions of argon gas；Mixture is cooled to room Temperature, adds methylene chloride, sodium acetate and 4-Aminobutanoicacid carbethoxy hydrochloride, and then mixture, which is protected from light, is vigorously stirred；Carbon is added Acid sodium solution, methylene chloride extraction；With magnesium sulfate drying, filtering, filtrate concentration gained residue is through column chromatography to pyrrole derivatives Object；
（2）PreparationNMethoxyl group-NMethyl -4- (1HPyrroles -1- base) butyramide process it is as follows：
It, will at 20 DEG CiThe tetrahydrofuran solution of-PrMgCl is added dropwise to 4- (1HPyrrole radicals) ethyl butyrate (6) and Me (MeO) in the solution of NHHCl, anhydrous THF；Mixture is slowly warming up to 0 DEG C, is stirred at 0 DEG C, then with saturation Ammonium chloride solution is quenched；Mixture is extracted with EA；Organic layer is merged, with anhydrous magnesium sulfate drying, filtering, filtrate concentration gained Residue is obtained through column chromatographyNMethoxyl group-NMethyl -4- (1HPyrroles -1- base) butyramide；
（3）Prepare 6- (1HPyrroles -1- base) hexyl -1- alkene -3- ketone process it is as follows：
At -20 DEG C, toNMethoxyl group-NMethyl -4- (1HPyrroles -1- base) butyramide tetrahydrofuran solution at 20 points Vinylimidazolium chloride magnesium is added dropwise in clock, reaction mixture stirs at this temperature；Under protection of argon gas, the water at -10 DEG C It is quenched；
The organic layer merged, anhydrous sodium sulfate drying are washed with ether aqueous layer extracted, saturated sodium chloride solution, is concentrated under reduced pressure slightly Product is directly used in next reaction；
（4）Prepare 6- (1HPyrroles -1- base) hexyl -1- alkene -3- alcohol process it is as follows：
At 0 DEG C, sodium borohydride is added in the methanol of seven water cerous chlorides, which is cooled to -78 DEG C, and adds dropwise Enter 6- (1HPyrroles -1- base) hexyl -1- alkene -3- ketone methanol solution；Reaction solution is stirred at -78 DEG C, and saturated ammonium chloride is added Simultaneously removal methanol is concentrated in aqueous solution quenching reaction；Water phase is extracted with ethyl acetate and combined organic layer, anhydrous sodium sulfate are dry, Filtering, filtrate concentration gained residue obtain 6- (1 through column chromatographyHPyrroles -1- base) hexyl -1- alkene -3- alcohol；
（5）Preparation (R, E)-methyl -4- hydroxyl -7- (1HPyrroles -1- base) heptyl -2- e pioic acid methyl ester process it is as follows：
(R)-6-(1HPyrroles -1- base) hexyl -1- alkene -3- alcohol is dissolved in methylene chloride, Grubbes bis- is added under room temperature For in catalyst and methacrylate；Reaction mixture is increased to 40 DEG C, is stirred 24 hours；Reaction mixture is concentrated to give To residue, obtain through column chromatography (R, E)-methyl -4- hydroxyl -7- (1HPyrroles -1- base) heptyl -2- e pioic acid methyl ester；
（6）Prepare (3aR, 10bR) -3a, 4,5,6- tetrahydro -1HFurans [3,2-c] pyrrolidines [1,2-a] azatropylidene -2 (10bH) -one process it is as follows：
At 0 DEG C, boron trifluoride ether is added to (R, E)-methyl -4- hydroxyl -7- (1HPyrroles -1- base) heptyl -2- alkene In the dichloroethane solution of sour methyl esters, reaction mixture is raised to room temperature and is stirred overnight；Reaction mixture is quenched with triethylamine, is stirred It mixes, organic layer is washed with water, and anhydrous sodium sulfate dries, filters, and filtrate concentration gained residue obtains (3a through column chromatographyR, 10bR) -3a, 4,5,6- tetrahydro -1HFurans [3,2-c] pyrrolidines [1,2-a] azatropylidene -2 (10bH) -one；
（7）Prepare (3aR, 10bR) -2- oxygen -1,3a, 4,5,6,10b- hexahydro -2HFurans [3,2-c] pyrrolidines [1, 2-a] azatropylidene -8- formaldehyde process it is as follows：
Under -10 DEG C, argon gas protective condition, oxalyl chloride solution is slowly dropped in dry DMF solution, it is brilliant to generate white After body, it is stirred at room temperature 15 minutes, methylene chloride is then added；By (3aR, 10bR) -3a, 4,5,6- tetrahydro -1H- Furans [3,2-c] pyrrolidines [1,2-a] azatropylidene -2 (10bH) -one is slowly dropped to reaction mixture after being dissolved in methylene chloride In, sodium acetate solution is added after stirring at room temperature, continues to be stirred at room temperature；Reaction mixture is extracted with dichloromethane, with saturation Sodium chloride solution washs combined organic layer, anhydrous sodium sulfate dries, filters, and filtrate concentration gained residue is obtained through column chromatography (3aR, 10bR) -2- oxygen -1,3a, 4,5,6,10b- hexahydro -2HFurans [3,2-c] pyrrolidines [1,2-a] azatropylidene- 8- formaldehyde；
（8）Prepare (3aR,10bR)-8-((E)-butyl -1- alkene -1- base) -1,3a, 4,5,6,10b- hexahydro -2HFurans The process of [3,2-c] pyrrolidines [1,2-a] azatropylidene -2- ketone is as follows：
Under the protection of argon gas, by (3aR, 10bR) -2- oxygen -1,3a, 4,5,6,10b- hexahydro -2HFurans [3, 2-c] pyrrolidines [1,2-a] azatropylidene -8- formaldehyde and 1- phenyl -5- (the third sulfonyl) -1HTetrazolium is dissolved in dry tetrahydrofuran In, -78 DEG C are subsequently cooled to, potassium hexamethyldisilazide is slowly added dropwise at this temperature, is finished, is stirred at this temperature Reaction 30 minutes, is then warmed to room temperature 12 h of reaction, and saturation NH is added at 0 DEG C4Cl solution is used with terminating reaction Methylene chloride extracts, washs the organic layer merged with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, and institute is concentrated in filtrate It obtains residue and obtains (3a through column chromatographyR,10bR)-8-((E)-butyl -1- alkene -1- base) -1,3a, 4,5,6,10b- six Hydrogen -2HFurans [3,2-c] pyrrolidines [1,2-a] azatropylidene -2- ketone；
（9）Prepare (3aR,10bR) -8- butyl -1,3a, 4,5,6,10b- hexahydro -2HFurans [3,2-c] pyrrolidines The process of [1,2-a] azatropylidene -2- ketone is as follows：
By (3aR,10bR)-8-((E)-butyl -1- alkene -1- base) -1,3a, 4,5,6,10b- hexahydro -2HFurans [3, 2-c] pyrrolidines [1,2-a] azatropylidene -2- ketone is dissolved in ethyl alcohol, palladium/carbon is added, under hydrogen effect, room temperature reaction；Reaction Mixture filtering removes palladium/carbon in solution with diatomite, and filtrate is concentrated to get (3aR, 10bR) -8- butyl -1,3a, 4, 5,6,10b- hexahydro -2HFurans [3,2-c] pyrrolidines [1,2-a] azatropylidene -2- ketone；
（10）Preparation (1R, 3aR, 10bR) -8- butyl -1- methyl-1,3a, 4,5,6,10b-hexahydro -2HFurans The process of [3,2-c] pyrrolidines [1,2-a] azatropylidene -2- ketone is as follows：
Under the protection of argon gas, by (3aR, 10bR) -8- butyl -1,3a, 4,5,6,10b- hexahydro -2HFurans [3, 2-c] pyrrolidines [1,2-a] azatropylidene -2- ketone is dissolved in dry tetrahydrofuran, is subsequently cooled to -78 DEG C, delays at this temperature It is slow that bis- (trimethyl silicon substrate) lithium amides are added dropwise, reaction flask is moved at 0 DEG C after reacting at this temperature and is reacted, it is then again cold But to -78 DEG C, iodomethane is added, the reaction was continued at this temperature；It is warmed to room temperature, saturation NH is added4Cl is reacted with terminating, It is extracted with dichloromethane, washs the organic layer merged with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, filtrate concentration Gained residue obtains (1 through column chromatographyR, 3aR, 10bR) -8- butyl -1- methyl-1,3a, 4,5,6,10b-six Hydrogen -2HFurans [3,2-c] pyrrolidines [1,2-a] azatropylidene -2- ketone；
（11）The process for preparing natural products parvistemonine is as follows：
By (1R, 3aR, 10bR) -8- butyl -1- methyl-1,3a, 4,5,6,10b-hexahydro -2HFurans [3,2-c] Pyrrolidines [1,2-a] azatropylidene -2- ketone is dissolved in ethyl alcohol, and potassium carbonate is added, is stirred at room temperature；Reaction mixture dichloro Methane extracts three times, merges organic phase, filtering, and filtrate concentration gained residue obtains natural products through column chromatography parvistemonine 。
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CN110237079A (en) * 2019-07-01 2019-09-17 山西大学 A kind of application of Stemona alkaloids analog
CN111423448A (en) * 2020-04-07 2020-07-17 山西大学 Stemona alkaloid skeleton-based small-molecule probe and preparation method and application thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110016041A (en) * 2019-05-13 2019-07-16 山西大学 A kind of Stemona alkaloids analog and preparation method and purposes
CN110237079A (en) * 2019-07-01 2019-09-17 山西大学 A kind of application of Stemona alkaloids analog
CN110237079B (en) * 2019-07-01 2021-05-14 山西大学 Application of radix stemonae alkaloid analogue
CN111423448A (en) * 2020-04-07 2020-07-17 山西大学 Stemona alkaloid skeleton-based small-molecule probe and preparation method and application thereof
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