CN104628803B - A kind of rape pollen alkali A and caper alkali D and the like total synthesis method - Google Patents
A kind of rape pollen alkali A and caper alkali D and the like total synthesis method Download PDFInfo
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Abstract
The present invention provides a kind of total synthesis method of natural products-rape pollen alkali A and caper alkali D with delaying cell aging activity.Using fructose as initiation material, by paired tosylate, pyrroles's substitution; the double methylolations of pyrroles, oxidation, selectivity deprotection; reduction and acid catalysis intramolecular are ketalization, and the reaction of Barton-McCombie deoxygenations and removing benzyl obtains final product rape pollen alkali A and caper alkali D.The total synthesis method of the present invention, using raw material cheap and easy to get, reaction dissolvent and reagent environmental pollution are small, high income, and alkaloid of synthesis and the like can be used for developing novel anti-inflammatory medicine Kangshuaining mixture.
Description
Technical field
The invention belongs to the field of chemical synthesis, it is related to the fully synthetic of a kind of rape pollen alkali A and caper alkali D and the like
Method.
Technical background
Pyrroles's sugar compounds have application, the treatment of such as neurogenic disease, U.S.'s food and medicine the different medical field more
Product management board approval on July 28th, 2010 Cuvposa (glycopyrrolate [glycopyrrolate]) oral administration solution 3 years old age for the treatment of is extremely
It is chronic caused by 16 years old children's neuropathies seriously to slaver over.In recent years, class uniqueness is found in the different parts of various plants
Sugared pyrrolidine alkaloid, 2003, Tu Peng flies to wait in the Radix Astragali isolated six new alkaloids compounds, and (such as Ma Xiaofeng was covered
The chemical constitution study of the ancient Radix Astragali, Shenyang Pharmaceutical University's thesis for the doctorate 2003), reporting for Wang Changhong etc. is carried in caper fruit
Take in thing, find to contain caper alkali A (capparisine A) ﹑ caper alkali B (capparisine B) ﹑ caper alkali
C (the alkaloids (CN101406497A) such as capparisine C) ﹑ caper alkali D.Recently, Cheng Yong is now waited from grass-leaved sweetflag rhizome
Isolated four alkaloids (CN101775026A), Zhang Peicheng etc. is reported to be found to contain rape pollen alkali A in Bee Pollen
(pollenopyrroside A), rape pollen alkali B (pollenopyrroside B).Consisting of fructose and pyrroles form miscellaneous
Spirane structure, virgin smooth monarch academician etc. has carried out systematic research to Radix Astragali alkali B and the Radix Astragali alkali C activity of fighting against senium and its mechanism.
Human embryonic lung diploid fibroblast (2BS) first from the built-in strain of state is replicability cell ageing model, with public in the world
The delaying cell aging medicine N-BETA-Alanyl-L-histidine recognized is compared, it is found that Radix Astragali alkali B and Radix Astragali alkali C not only substantially promotees under relatively low concentration
Enter cell propagation, the cell of medicine culture can increase by 16,19 generations for age, and in higher concentrations without obvious cytotoxicity
(Capital University of Medical Sciences's journal, 2007,28 (2):145-150.).Wang Changhong etc. is to the Capparis spinosa extract containing caper alkali B
The test of pesticide effectiveness prove that it has good analgesia and anti-inflammatory activity, available for treatment rheumatic arthritis, gout and scapulohumeral periarthritis
Proved etc. disease, and through acute toxicity test, the extract toxicity very low [Shanghai Univ. of Traditional Chinese Medicine's journal, 2009 (1):38-
41].The activity to grass-leaved sweetflag alkali A and grass-leaved sweetflag alkali B anti diabetes and kidney disease that Cheng Yong is now waited is studied, it is found that high sugar is lured
The mesangial cell ROS led generation is substantially suppressed by grass-leaved sweetflag alkali A, and grass-leaved sweetflag alkali B also shows slight depression effect.Due to
With good anti-inflammatory, senile-resistant efficacy, and there is certain curative effect to nephrosis, this alkaloid is received significant attention.
Natural sugared pyrrolidine alkaloid content is few, it is difficult to extracts, is ppm grades, makes sugared pyrrolidine alkaloid further
Further investigation become further difficult.The sugared pyrrolidine alkaloid of separation is extracted from crude drug, it is necessary to which active compound amount is big, price is held high
It is expensive.
The content of the invention
It is former by starting of fructose the invention provides rape pollen alkali A and caper alkali D and the like synthetic method
Material, by paired tosylate, pyrroles's substitution, the double methylolations of pyrroles, oxidation, selectivity deprotection, reduction and acid catalysis
Intramolecular is ketalization, and the reaction of Barton-McCombie deoxygenations and removing benzyl obtains final product rape pollen alkali A
With caper alkali D.
Technical scheme is as follows：
A kind of rape pollen alkali A and caper alkali D synthetic method, comprises the following steps,
With 2,3；4,5- diacetone fructoses are raw material, and 1 hydroxyl is esterified, compound II is obtained：The reaction is to use
Good leaving group is to 2,3；The exposed hydroxyl of 4,5- diacetone fructoses is esterified, and compound II is 2,3；4,5- diacetones
1 p-methyl benzenesulfonic acid ester, imidazole sulfonic acid ester or the methanesulfonates of fructose；
Under alkalescence condition, compound II carries out nucleophilic substitution with pyrroles and obtains compound III：Selected solvent is DMF
Or toluene, alkalescence condition can provide by NaH, KOH or NaOH, and temperature is 100-150 DEG C；
Compound III double methylolations in formalin obtain compound IV；Temperature be 20-120 DEG C, solvent be water,
Ethanol, one kind of methanol or mixed solvent, methylolation reagent are paraformaldehyde or formalin solution, and alkaline reagent is carbonic acid
Potassium, sodium carbonate or calcium carbonate；
The double hydroxyl oxidations of compound IV obtain double formyl adduct V, and solvent is acetone, ethyl acetate or DMSO, oxidation
Agent is manganese dioxide, the oxide of chromium or periodate oxidation thing, and temperature is 20-50 DEG C；
The deprotection of compound V chosen property obtains compound VI, using a kind of method in following：
A, from Bronsted acid, collocation solvent is one kind or mixed solvent in methanol, ethanol, and temperature is ice bath or room temperature,
Obtain compound VI；
B, from lewis acid, collocation solvent is one kind or mixed solvent in methanol, ethanol, and temperature is ice bath or room
Temperature, obtains compound VI；
C, from DDQ, solvent is acetonitrile and water, and temperature is 20-120 DEG C, obtains compound VI；
Compound VI is protected with neopentyl glycol to aldehyde radical, obtains compound VII：The reaction dissolvent of the reaction is dichloro
Methane, catalysis is using p-methyl benzenesulfonic acid, sulfuric acid or hydrochloric acid, and temperature is room temperature or ice bath；
Benzyl protection is carried out to compound VII two hydroxyls, compound VIII is obtained；The solvent of the reaction be DMF or
Dichloromethane, benzylating reagent is BnCl or BnBr, and temperature is 20-60 DEG C；
Compound VIII is under sour water effect, and the protection of removing isopropyl subunit and neopentyl glycol protection obtain compound IX；Should
Reaction is flowed back or stirred at normal temperatures using trifluoroacetic acid and water in aqueous acetic acid；
Compound IX reduces one of aldehyde radical and obtains compound X into hydroxyl, the reducing agent of the reaction using sodium borohydride,
Lithium aluminium hydride reduction or sodium triacetoxy borohydride, in methanol, ethanol or tetrahydrofuran/aqueous systems；
Cyclization is into compound XI and compound XIV under acid effect by compound X, and the reaction acid reagent is used to toluene sulphur
Acid, sulfamic acid, camphorsulfonic acid, hydrochloric acid or sulfuric acid, solvent are dichloromethane；
Compound XI or the exposed hydroxyls of compound XIV are reacted by Barton-McCombie to be removed；The catalysis of the reaction
Agent is imidazoles, and solvent is tetrahydrofuran, compound XI or compound XIV and sodium hydride, and carbon disulfide and iodomethane reaction are into Huang
Ortho esters, isolates and purifies to obtain compound XII or compound XV, is solvent in dioxane, benzoyl peroxide draws for free radical
Agent is sent out, the lower removing xanthate of triethyl silicane effect obtains compound XIII or compound XVI；
Compound XIII or compound XVI removes benzyl under lewis acid effect, obtains final product rape pollen alkali A
Or caper alkali D：The reaction is using lewis acid as benzyl oxide lytic reagent, and described lewis acid uses butter of tin or four
Titanium chloride.
A kind of synthetic method of rape pollen alkali A and caper alkali D analog, this is used as benzyl oxide using lewis acid
Lytic reagent, described lewis acid uses butter of tin or titanium tetrachloride.
The total synthesis method of the present invention, using raw material cheap and easy to get, reaction dissolvent and reagent environmental pollution are small, yield
Height, the alkaloid of synthesis and the like can be used for developing novel anti-inflammatory medicine Kangshuaining mixture.
Embodiment
Further detailed description is done to the present invention with reference to embodiment, but the implementation of the present invention is not limited to this.
Weigh 15.19g sodium hydrides to be placed in 500mL three-necked flasks, dissolved with 50mLDMF, measure 10mL pyrroles, use 60mL
DMF dissolves, and the DMF solution (dripping for about 3 seconds one) of pyrroles is slowly added dropwise under ice bath in flask, 30.58g compounds are weighed after dripping off
II, is dissolved with 60mL DMF, and material liquid is slowly added dropwise and (dripped within about 3 seconds one) under ice bath and in three-necked flask, is transferred to 40 DEG C of oil baths
Lower reaction 1h, rise oil bath temperature reacts 4-5 days, TLC (P to 135 DEG C:E=3:1) detection reaction is basically completed, and is added a small amount of
In methanol and NaH, to bubble-free generation, vacuum distillation removes DMF, and the multiple extractive reaction liquid of ethyl acetate, organic phase is transferred to eggplant
Rotary evaporation removes most of solvent in shape bottle.Silica gel is mixed, Tan solid powder, silica gel column chromatography, dry method loading, oil is obtained
Ether:Ethyl acetate=8:1 elution, obtains white solid 16.18g (4), yield 70.9%.
80mL deionized waters are measured in 250mL three-necked flasks, 10.00g whites K is weighed2CO3Solid is added, ultrasonic dissolution
After sequentially add 50mL formalins and 5g compound II, be placed in microwave reactor, add reflux, be stirred at reflux reaction
40 minutes 2 hours, set response parameter be：80 DEG C of reaction temperature, 40 minutes reaction time 2 hour, reaction power 500W.Reaction
Liquid is transferred in 250mL separatory funnels, the extractive reaction liquid of ethyl acetate 100mL × 3, anhydrous sodium sulfate drying organic layer.Suction filtration
Desalination, rotary evaporation removes solvent and obtains crude product 5.Crude product IV is shifted into 100mL conical flasks with proper amount of acetone, adds 10-
15g manganese dioxide, stirring at normal temperature is reacted 2 days, and suction filtration removes manganese dioxide, and rotary evaporation filtrate removes solvent, silica gel column chromatography, stone
Oily ether:Ethyl acetate=4:1 elution, obtains Tan solid 5.14g (V), two step total recoverys 87%.1H NMR(400MHz,
CDCl3) δ 9.89 (s, 2H), 6.98 (s, 2H), 5.25 (d, J=14.5Hz, 1H), 5.05 (d, J=14.5Hz, 1H), 4.54
(dd, J=7.9,2.6Hz, 1H), 4.37 (d, J=2.6Hz, 1H), 4.17 (dd, J=7.9,2.0Hz, 1H), 3.84 (dd, J=
13.1,2.0Hz, 1H), 3.72 (d, J=13.1Hz, 1H), 1.46 (s, 3H), 1.40 (s, 3H), 1.31 (s, 3H), 1.19 (s,
3H).13C NMR(100MHz,CDCl3)δ181.9,137.1,119.7,109.0,108.8,101.6,71.5,70.2,70.3,
61.4,50.4,26.3,25.8,24.6,23.6.HRMS(ESI)calcd for C18H24NO7[M+H]+366.1553,
found366.1547.
54mL acetonitriles shift 1g compounds V to 100mL reaction bulbs, dissolving stirring, sequentially add 6mL deionized waters and
124mg DDQ, reaction unit is transferred to back flow reaction 7h under 80 DEG C of oil baths, and rotary evaporation is gone out solvent, and 90mL ethyl acetate is molten
Solution is transferred to 250mL separatory funnels, and 2% sodium hydroxide solution is washed 3 times, anhydrous sodium sulfate drying organic layer, suction filtration desalination.Rotation
Turn evaporation of solvent, silica gel column chromatography, petroleum ether:Ethyl acetate=1:1, product 756mg (VI) is obtained, yield is 85%.1H
NMR (400MHz, CDCl3) δ 9.82 (s, 2H), 7.01 (s, 2H), 5.25 (H-1, d, J=14.4Hz, 1H), 5.20 (H-1, d, J
=14.4Hz, 1H), 4.27 (H-4, dd, J=5.5,3.0Hz, 1H), 4.16 (H-3, d, J=3.0Hz, 1H), 4.01 (H-5,
Dd, J=4.5,5.5Hz, 1H), 3.84 (H-6, dd, J=12.3,4.5Hz, 1H), 3.77 (H-6, dd, J=12.3,5.5Hz,
1H),1.43(s,3H),1.22(s,3H).13C NMR(100MHz,CDCl3),δ182.4,137.2,121.5,110.5,
101.3,77.0,66.2,63.7,63.5,49.1,27.0,25.0.HRMS(ESI)calcd forC15H19NO7Na[M+Na]+
348.1059,found 348.1058.
Dichloromethane transfer 800mg raw materials (VI) to 100mL reaction bulbs, stirring and dissolving adds 159.2mg neopentyl glycols
(NPG), ultrasonic dissolution, adds 50mg p-methyl benzenesulfonic acid, normal-temperature reaction 1h adds sodium acid carbonate and neutralized, until bubble-free generation,
Suction filtration desalination, rotary evaporation removes solvent.Silica gel column chromatography, petroleum ether:Ethyl acetate=1:1 elution, obtains 982mg whites solid
Body VII, yield is 97%.1H NMR(400MHz,CDCl3) δ 9.45 (s, 1H), 7.00 (d, J=4.2Hz, 1H), 6.57 (d, J
=4.2Hz, 1H), 5.82 (s, 1H), 4.25 (d, J=2.7Hz, 1H), 4.23-4.17 (m, 1H), 4.00 (dd, J=12.3,
4.0Hz, 1H), 3.91 (dt, J=6.0,3.9Hz, 1H), 3.67 (d, J=11.3Hz, 1H), 3.62 (d, J=11.3Hz, 1H),
1.55(s,3H),1.49(s,3H),1.40(s,3H),1.36(s,3H).HRMS(ESI)calcd forC20H30NO8[M+H]+
412.1971,found 412.1969.
With DMF transfer 900mg raw materials (VII) to 100mL reaction bulbs, stirring and dissolving adds NaH (35%) 450mg, liquid relief
Rifle is added dropwise to BnCl 600 μ L, normal-temperature reaction 3h, is added dropwise in few drops of pipe methanol and NaH, until bubble-free generation, rotary evaporation is removed
Solvent, 100mL ethyl acetate is transferred to 250mL separatory funnels, the water washing of 80mL × 3, anhydrous sodium sulfate drying organic layer, suction filtration
Desalination, rotary evaporation removes solvent, silica gel column chromatography, petroleum ether:Ethyl acetate=4:1,1.138g white solid VIII are obtained,
Yield 88%.1H NMR(400MHz,CDCl3) δ 9.49 (s, 1H), 7.42-7.27 (m, 10H), 6.85 (d, J=4.1Hz, 1H),
6.46 (d, J=4.1Hz, 1H), 5.71 (s, 1H), 4.87 (d, J=11.9Hz, 1H), 4.74 (d, J=11.9Hz, 1H),
4.63-4.53 (m, 4H), 4.23 (d, J=3.5Hz, 1H), 4.16 (t, J=2.8Hz, 1H), 4.04 (dd, J=10.7,
9.3Hz, 1H), 3.98-3.88 (m, 1H), 3.80 (dd, J=10.9,3.9Hz, 1H), 3.67 (ddd, J=20.7,11.0,
2.6Hz, 2H), 3.52 (d, J=10.5Hz, 2H), 1.39 (s, 3H), 1.26 (s, 3H), 1.21 (s, 3H), 0.74 (s, 3H)13C
NMR(100MHz,CDCl3)δ180.0,138.1,133.8,128.8,1286,128.5,127.8,127.8,127.5,111.0,
109.0,102.5,96.0,78.1,77.2,73.6,72.5,72.4,71.6,60.9,47.4,463,30.3,27.9,26.1,
22.9,21.9.HRMS(ESI)calcd for C34H42NO8[M+H]+592.2910,found 592.2914.
Prepare deionized water:Acetic acid=1:1 common 60mL solvents, transfer 1g raw materials (VIII) to 100mL reaction bulbs are stirred molten
Solution, back flow reaction 2 days under 100 DEG C of oil baths, rotary evaporation removes solvent, silica gel column chromatography, petroleum ether:Ethyl acetate=1:1 washes
It is de-, obtain colorless oil 728mg (IX), yield 92.5%.1H NMR(400MHz,CDCl3)δ9.83(s,2H),7.48–
7.27 (m, 10H), 7.00 (s, 2H), 5.09 (H-1, d, J=14.6Hz, 1H), 4.89 (H-1, d, J=14.6Hz, 1H),
4.72-4.63 (m, 1H), 4.60 (d, J=12.0Hz, 1H), 4.57-4.46 (m, 1H), 4.21 (s, 1H), 4.16-4.05 (m,
1H), 4.03 (H-3, d, J=9.6Hz, 1H), 3.87 (ddd, J=22.3,7.0,2.2Hz, 1H), 3.81-3.72 (m, 1H),
3.70 (s, 1H), 3.64 (dd, J=9.5,3.1Hz, 1H) .HRMS (ESI) calcd for C26H28NO7[M+H]+466.1866,
found 466.1872.
10.2mg NaBH are added portionwise to 100mL reaction bulbs in 10mL methanol transferase 45s 00mg compounds IX4(96%), stir
Mix and 30min is reacted under dissolving, ice bath, 30mL deionized water dissolvings are transferred to 100mL separatory funnels, the dichloromethane extraction of 30mL × 3
Take, organic phase anhydrous sodium sulfate drying, suction filtration desalination, rotary evaporation removes solvent, silica gel column chromatography, petroleum ether:Acetic acid second
Ester=1:1 washing, obtains colorless oil as product 450mg (X), yield 90%.
Dichloromethane shifts 400mg compounds X to 100mL reaction bulbs, the stirring of 5mg p-methyl benzenesulfonic acid is added under ice bath molten
10h is reacted under solution, ice bath, is added in appropriate saturated sodium bicarbonate solution and PTSA, until without the full generation of gas, 30mL deionized waters
Solution transfer is to 100mL separatory funnels, the dichloromethane extraction of 30mL × 3, organic phase anhydrous sodium sulfate drying, suction filtration desalination,
Rotary evaporation removes solvent, petroleum ether:Ethyl acetate=3:1 elution, obtain white solid XI and XIV be respectively 84mg,
256mg, yield 22% and 67%.1H NMR(400MHz,CDCl3)δ9.44(s,1H),7.39–7.26(m,10H),6.92(d,J
=4.1Hz, 1H), 6.01 (d, J=4.1Hz, 1H), 5.04 (d, J=15.5Hz, 1H), 4.90 (d, J=15.5Hz, 1H),
4.84 (d, J=14.7Hz, 1H), 4.71-4.64 (m, 3H), 4.61 (d, J=12.2Hz, 1H), 4.31 (d, J=14.1Hz,
2H), 4.20 (d, J=7.8Hz, 1H), 4.01 (dd, J=12.3,5.4Hz, 1H), 3.85 (ddd, J=5.4,3.1,2.7Hz,
1H), 3.72 (dd, J=7.8,3.1Hz, 1H), 3.54 (dd, J=12.3,2.7Hz, 1H)13C NMR(100MHz,CDCl3)δ
178.8,137.9,137.9,135.1,131.3,128.9,128.5,128.45,127.9,127.8,127.8,124.4,
104.8,96.9,77.33,76.7,72.3,71.6,71.5,71.3,65.6,61.6,58.4,29.7.HRMS(ESI)calcd
for C26H28NO6[M+H]+450.1917,found 450.1908.
200mg XI are dissolved under anhydrous tetrahydro furan, ice bath and stirred, 5mg imidazoles and 73mg NaH is added, continue to stir
20 minutes, 81 μ L CS2 are added, continues to stir, adds 50 μ L CH3I, continue to react 30 minutes, are added in methanol and NaH, second
Acetoacetic ester and moisture liquid, water layer ethyl acetate extraction (3*50mL) merge organic layer, dry.Silica gel column chromatography is separated, oil
Ether:Ethyl acetate=3:1 washing, obtains faint yellow oil product XII (221mg, 92%).1H NMR(400MHz,CDCl3)δ
9.44 (s, 1H), 7.50-7.26 (m, 6H), 6.90 (d, J=4.1Hz, 1H), 6.10 (d, J=3.2Hz, 1H), 6.01 (d, J=
4.1Hz, 1H), 4.89 (dd, J=7.6,4.1Hz, 2H), 4.76-4.70 (m, 1H), 4.64 (d, J=14.3Hz, 1H), 4.50
(d, J=11.9Hz, 1H), 4.44 (d, J=11.8Hz, 1H), 4.10 (t, J=10.4Hz, 1H), 4.03 (t, J=3.0Hz,
1H), 3.96 (d, J=14.3Hz, 1H), 3.83-3.73 (m, 1H), 3.68 (dd, J=10.4,4.4Hz, 1H), 2.59 (s,
2H).HRMS(ESI)calcd for C28H30NO6S2[M+H]+100mg XII are dissolved in by 540.1515, found 540.1510.
Dry 5mL dioxane, adds 148 μ L triethyl silicanes, is warming up to 90 DEG C, and the dioxy six of 45mg benzoyl peroxides is added dropwise
Ring solution.It is warming up to 100 DEG C to react 2 hours, is cooled to room temperature.The 8%NaOH aqueous solution is added to be stirred overnight.Ethyl acetate and water
Divide liquid, water layer ethyl acetate extraction (3*50mL) merges organic layer, dried.Silica gel column chromatography is separated, petroleum ether:Ethyl acetate
=4:1 washing, obtains colorless oil as product XIII (46mg, 72%).1H NMR(400MHz,CDCl3)δ9.44(s,1H),7.46–
7.27 (m, 5H), 6.91 (d, J=4.1Hz, 1H), 6.01 (d, J=4.0Hz, 1H), 4.83 (d, J=11.2Hz, 1H), 4.57
(d, J=14.0Hz, 1H), 4.47 (d, J=11.3Hz, 1H), 4.02 (d, J=14.0Hz, 1H), 3.96 (d, J=3.2Hz,
1H), 3.81 (dd, J=11.5,6.8Hz, 1H), 3.66-3.56 (m, 1H), 2.45 (dd, J=15.0,3.5Hz, 1H), 1.78
(dd, J=15.0,3.5Hz, 1H) δ C (101MHz, CDCl3) 178.86,137.79,134.85,131.01,128.55,
127.99,127.97,124.38,104.89,93.26,72.74,70.69,65.88,60.98,57.60,51.80,
33.86.HRMS(ESI)calcd for C19H22NO5[M+H]+344.1498,found 344.1494.
50mg XIII are dissolved in CH2Cl2Ice salt bath is cooled to -10 DEG C.Add 25 μ L TiCl4, continue to stir 2 hours.Add
Saturation Na2CO3The aqueous solution, diatomite drainage desalination, ethyl acetate extraction (3 × 20mL), anhydrous sodium sulfate drying, silica gel column layer
Analysis separation, petroleum ether:Ethyl acetate=1:10 washings, obtain white solid rape pollen alkali A (32mg, 87%).1H NMR
(400MHz,CDCl3) δ 9.46 (s, 1H), 6.92 (d, J=4.1Hz, 1H), 6.03 (d, J=4.0Hz, 1H), 4.88 (s, 2H),
4.58 (d, J=14.2Hz, 1H), 4.07 (d, J=14.2Hz, 1H), 3.76 (d, J=8.2Hz, 1H), 3.59 (s, 1H), 2.30
(dd, J=14.8,3.1Hz, 1H), 2.00 (dd, J=14.8,3.4Hz, 2H)13C NMR(100MHz,CDCl3)δ178.9,
131.2,123.9,105.0,94.6,77.2,67.0,65.7,60.2,57.89,51.6,37.5.HRMS(ESI)calcd for
C12H16NO5[M+H]+254.1028,found 254.1024.
Claims (2)
1. a kind of rape pollen alkali A and caper alkali D total synthesis method, its feature comprise the following steps
1) with leaving group to 2,3；The exposed hydroxyl of 4,5- diacetone fructoses be esterified obtaining compound II, and compound II is
2,3；1 p-methyl benzenesulfonic acid ester, imidazole sulfonic acid ester or the methanesulfonates of 4,5- diacetone fructoses；
2) under alkalescence condition, compound II carries out nucleophilic substitution with pyrroles and obtains compound III；Solvent be DMF or toluene,
Alkalescence condition is provided by NaH, KOH or NaOH, and temperature is 100-150 DEG C；
3) compound III is in formalin, and double methylolations obtain compound IV, and temperature is 20-120 DEG C, and solvent is water, second
Alcohol, one kind of methanol or mixed solvent, methylolation reagent are paraformaldehyde or formalin solution, and alkali is potassium carbonate, carbonic acid
Sodium or calcium carbonate；
4) the double hydroxyl oxidations of compound IV obtain double formyl adduct V；Organic solvent is acetone, ethyl acetate or DMSO, oxygen
Agent is manganese dioxide, the oxide of chromium or periodate oxidation thing, and temperature is 20-50 DEG C；
5) compound V chosen property deprotection, using one kind in following：
A, from Bronsted acid, collocation solvent is one kind or mixed solvent in methanol, ethanol, and temperature is ice bath or room temperature, is obtained
Compound VI；
B, from lewis acid, collocation solvent is one kind or mixed solvent in methanol, ethanol, and temperature is ice bath or room temperature, is obtained
To compound VI；
C, from DDQ, solvent is acetonitrile and water, and temperature is 20-120 DEG C, obtains compound VI；
6) compound VI is protected with neopentyl glycol to aldehyde radical, obtains compound VII, and reaction dissolvent is dichloromethane, catalysis
Using p-methyl benzenesulfonic acid, sulfuric acid or hydrochloric acid, room temperature or ice bath；
7) compound VII two hydroxyls are carried out with benzyl protection, solvent is DMF, dichloromethane, benzylating reagent be BnCl or
BnBr, temperature is 20-60 DEG C, obtains compound VIII；
8) compound VIII is under sour water effect, and the protection of removing isopropyl subunit and neopentyl glycol protection obtain compound IX, in vinegar
Flow back or stirred at normal temperatures using trifluoroacetic acid and water in aqueous acid；
9) aldehyde radical is reduced into hydroxyl and obtains compound X in compound IX, reducing agent using sodium borohydride, lithium aluminium hydride reduction or
Sodium triacetoxy borohydride, in methanol, ethanol or tetrahydrofuran/aqueous systems；
10) cyclization is into XI and XIV under acid effect by compound X, and acid reagent uses p-methyl benzenesulfonic acid, sulfamic acid, camphor sulphur
Acid, hydrochloric acid or sulfuric acid, solvent is dichloromethane；
11) compound XI or the exposed hydroxyls of compound XIV are reacted by Barton-McCombie removes, and catalyst is imidazoles,
Solvent is tetrahydrofuran, with sodium hydride, and carbon disulfide and iodomethane reaction isolate and purify to obtain XII or XV, two into xanthate
The ring of oxygen six is solvent, and benzoyl peroxide is radical initiator, and the lower removing xanthate of triethyl silicane effect obtains chemical combination
Thing XIII or XVI；
12) XIII or XVI removes benzyl under lewis acid effect, obtains final product rape pollen alkali A or caper alkali
D；Lewis acid is used as benzyl oxide lytic reagent
2. a kind of synthetic method of rape pollen alkali A and caper alkali D analog, its feature comprises the following steps：
,
Described lewis acid uses butter of tin or titanium tetrachloride.
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| CN108997448B (en) * | 2018-07-17 | 2021-03-12 | 大连理工大学 | Total synthesis method and application of pyranose ring pyrrole spiroketal alkaloid |
| CN109897051B (en) * | 2019-03-31 | 2021-07-09 | 白银乐天园化学有限责任公司 | Preparation method of 3-oxa-8-aza-bicyclo [3,2,1] octane hydrochloride |
| CN116509870A (en) * | 2023-03-29 | 2023-08-01 | 大连理工大学 | New use of rape pollen alkaloid A in neuroprotection and brain disease prevention and treatment |
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| US3691197A (en) * | 1970-12-17 | 1972-09-12 | Bernard Beau Brown | Preparation of 1-substituted-3-chloropyrrolidines |
| WO2000020414A1 (en) * | 1998-10-02 | 2000-04-13 | Combichem, Inc. | Piperidyloxadiazoles as dopamine receptor antagonists |
| CN101406497A (en) * | 2008-11-26 | 2009-04-15 | 上海中医药大学 | Capparis spinosa extract as well as preparation method and application thereof |
| CN101775026A (en) * | 2010-02-03 | 2010-07-14 | 中国科学院昆明植物研究所 | Spiro alkaloid compound, medicinal composition comprising same and preparation method and application thereof |
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| US3691197A (en) * | 1970-12-17 | 1972-09-12 | Bernard Beau Brown | Preparation of 1-substituted-3-chloropyrrolidines |
| WO2000020414A1 (en) * | 1998-10-02 | 2000-04-13 | Combichem, Inc. | Piperidyloxadiazoles as dopamine receptor antagonists |
| CN101406497A (en) * | 2008-11-26 | 2009-04-15 | 上海中医药大学 | Capparis spinosa extract as well as preparation method and application thereof |
| CN101775026A (en) * | 2010-02-03 | 2010-07-14 | 中国科学院昆明植物研究所 | Spiro alkaloid compound, medicinal composition comprising same and preparation method and application thereof |
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