CN104628803A - Total synthesis method for rape pollen alkali A and caper alkali B and analogues thereof - Google Patents
Total synthesis method for rape pollen alkali A and caper alkali B and analogues thereof Download PDFInfo
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- GENSDBQITRMPBU-DYXQDRAXSA-N OCc1ccc(C=O)[n]1CC([C@H]([C@@H]1OCc2ccccc2)O)(O)OC[C@H]1OCc1ccccc1 Chemical compound OCc1ccc(C=O)[n]1CC([C@H]([C@@H]1OCc2ccccc2)O)(O)OC[C@H]1OCc1ccccc1 GENSDBQITRMPBU-DYXQDRAXSA-N 0.000 description 1
- BCOMTSZZRMBKDL-XPGKHFPBSA-N O[C@@H]([C@@H]([C@@H](CO1)OCc2ccccc2)OCc2ccccc2)[C@@]11OCc2ccc(C=O)[n]2C1 Chemical compound O[C@@H]([C@@H]([C@@H](CO1)OCc2ccccc2)OCc2ccccc2)[C@@]11OCc2ccc(C=O)[n]2C1 BCOMTSZZRMBKDL-XPGKHFPBSA-N 0.000 description 1
- BCOMTSZZRMBKDL-FXSWLTOZSA-N O[C@@H]([C@@H]([C@@H](CO1)OCc2ccccc2)OCc2ccccc2)[C@]11OCc2ccc(C=O)[n]2C1 Chemical compound O[C@@H]([C@@H]([C@@H](CO1)OCc2ccccc2)OCc2ccccc2)[C@]11OCc2ccc(C=O)[n]2C1 BCOMTSZZRMBKDL-FXSWLTOZSA-N 0.000 description 1
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Abstract
The invention provides a total synthesis method for natural products such as rape pollen alkali A and caper alkali B with the activity of delaying cell aging. The method comprises the following steps: taking fructose as an initial raw material, performing tosylate formation, pyrrole substitution, pyrrole bi-hydroxymethylation, oxidation and selective deprotection, reducing and performing acid catalysis on intramolecular ketalation, carrying out a Barton-McCombie deoxidation reaction and a benzyl removal reaction, thereby obtaining the final products such as the rape pollen alkali A and caper alkali B. According to the total synthesis method disclosed by the invention, cheap and readily available raw materials are adopted, the environmental pollution caused by the reaction solvents and reagents is slight, the yield is high, and the synthesized alkaloids and analogues thereof can be used for developing novel anti-inflammatory agents and anti-aging drugs.
Description
Technical field
The invention belongs to the field of chemical synthesis, relate to the total synthesis method of a kind of Pollen Brassicae campestris alkali A and Hyoscyamus niger L alkali B and analogue.
Technical background
Glycopyrrolate compound has application in different medical field more, as the treatment etc. of nervous system disease, what U.S. food and approval in drug administration on July 28th, 2010 Cuvposa (glycopyrrolate [glycopyrrolate]) oral liquid treatment 3 years old to 16 years old age children's neuropathy caused chronicly seriously slavers over.In recent years, the sugared quinazoline alkaloid of a class uniqueness is found in the different sites of various plants, 2003, Tu Pengfei etc. be separated in the Radix Astragali obtain six new alkaloids compounds (Ma Xiaofeng etc. the chemical constitution study of Radix Astagali, Shenyang Pharmaceutical University's Ph D dissertation 2003), Wang Changhong etc. reports in Hyoscyamus niger L fruit extract, find containing containing Hyoscyamus niger L alkali A (capparisine A) ﹑ Hyoscyamus niger L alkali B (the capparisine B) ﹑ Hyoscyamus niger L alkali C (alkaloid (CN101406497A) such as capparisine C) ﹑ Hyoscyamus niger L alkali D.Recently, Cheng Yong now waits separation from Rhizome of Grass leaf Sweelflag rhizome to obtain four alkaloids (CN101775026A), and Zhang Peicheng etc. report in bee pollen and find containing Pollen Brassicae campestris alkali A (pollenopyrroside A), Pollen Brassicae campestris alkali B (pollenopyrroside B).It consists of fructose and pyrroles forms assorted spirane structure, and virgin smooth monarch academician etc. have carried out systematic research to the activity of fighting against senium of Radix Astragali alkali B and Radix Astragali alkali C and mechanism thereof.First select the human embryonic lung diploid fibroblast (2BS) of the built-in strain of state for replicability cell aging model, compare with the delaying cell aging medicine N-BETA-Alanyl-L-histidine of generally acknowledging in the world, find that Radix Astragali alkali B and Radix Astragali alkali C not only obviously promotes cell proliferation under lower concentration, medicine cultured cells can increase by 16 for age, 19 generations, and in higher concentrations without obvious cytotoxicity (Capital University of Medical Sciences's journal, 2007,28 (2): 145-150.).The test of pesticide effectiveness to the Capparis spinosa extract containing Hyoscyamus niger L alkali B such as Wang Changhong proves that it has good analgesia and anti-inflammatory activity, can be used for treating rheumatic arthritis, the disease such as gout and scapulohumeral periarthritis, and prove through acute toxicity test, this extract toxicity very low [Shanghai Univ. of Traditional Chinese Medicine's journal, 2009 (1): 38-41].The activity of the anti diabetes and kidney disease to Rhizome of Grass leaf Sweelflag alkali A and Rhizome of Grass leaf Sweelflag alkali B that Cheng Yong now waits is studied, and find that the generation of the mesangial cell ROS of high sugar induction is obviously suppressed by Rhizome of Grass leaf Sweelflag alkali A, Rhizome of Grass leaf Sweelflag alkali B also shows slight retarding effect.Owing to having good anti-inflammatory, senile-resistant efficacy, and have certain curative effect to ephrosis, this alkaloid is subject to extensive concern.
Natural sugared quinazoline alkaloid content is few, is difficult to extract, and is ppm level, makes the further further investigation of sugared quinazoline alkaloid become difficulty further.From crude drug, extraction and isolation sugar quinazoline alkaloid, needs former dose large, expensive.
Summary of the invention
The invention provides Pollen Brassicae campestris alkali A and Hyoscyamus niger L alkali B and analogue synthetic method; take fructose as starting raw material; pass through into p-toluenesulfonic esters; pyrroles replaces; the two methylolation of pyrroles, oxidation, selectivity deprotection; reduction and acid catalysis molecule inside contract ketonize, Barton-McCombie deoxygenation and remove benzyl be obtained by reacting final product Pollen Brassicae campestris alkali A and Hyoscyamus niger L alkali B.
Technical scheme of the present invention is as follows:
A synthetic method of Pollen Brassicae campestris alkali A and Hyoscyamus niger L alkali B, comprises the following steps,
With 2,3; 4,5-diacetone fructose is raw material, carries out esterification, obtain Compound II per to 1 hydroxyl: this reaction is with good leavings group to 2,3; The hydroxyl that 4,5-diacetone fructose is exposed carries out esterification, and Compound II per is p-toluenesulfonic esters, imidazole sulfonic acid ester or methanesulfonates;
Under alkaline condition, Compound II per and pyrroles carry out nucleophilic substitution reaction and obtain compound III: selected solvent is DMF or toluene, and alkaline condition can be provided by NaH, KOH or NaOH, and temperature is 100-150 DEG C;
Compound III two methylolation in formaldehyde solution obtains compound IV; Temperature is 20-120 DEG C, and solvent is water, ethanol, the one of methyl alcohol or mixed solvent, and methylolation reagent is paraformaldehyde or formalin solution, and alkaline reagents is salt of wormwood, sodium carbonate or calcium carbonate;
The two hydroxyl oxidize of compound IV obtains two formyl adduct V, and solvent is acetone, ethyl acetate or DMSO, and oxygenant is Manganse Dioxide, the oxide compound of chromium or periodate oxidation thing, and temperature is 20-50 DEG C;
Compound V obtains compound VI through selectivity deprotection, adopt following in a kind of method:
A, select protonic acid, collocation solvent is one in methyl alcohol, ethanol or mixed solvent, and temperature is ice bath or room temperature, obtains compound VI;
B, select Lewis acid, collocation solvent is one in methyl alcohol, ethanol or mixed solvent, and temperature is ice bath or room temperature, obtains compound VI;
C, select DDQ, solvent is acetonitrile and water, and temperature is 20-120 DEG C, obtains compound VI;
Compound VI neopentyl glycol is protected aldehyde radical, obtains compound VI I: the reaction solvent of this reaction is methylene dichloride, and catalysis adopts tosic acid, sulfuric acid or hydrochloric acid, and temperature is room temperature or ice bath;
Benzyl protection is carried out to two hydroxyls of compound VI I, obtains compound VI II; The solvent of this reaction is DMF or methylene dichloride, and benzylating reagent is BnCl or BnBr, and temperature is 20-60 DEG C;
Compound VI II under sour water effect, remove isopropyl subunit protection and neopentyl glycol protect obtain Compound I X; This reaction refluxes or adopts trifluoroacetic acid and water to stir at normal temperatures in aqueous acetic acid;
Compound I X reduces one of them aldehyde radical and becomes hydroxyl to obtain compounds X, and the reductive agent of this reaction adopts sodium borohydride, lithium aluminum hydride or sodium triacetoxy borohydride, in methyl alcohol, ethanol or tetrahydrofuran (THF)/aqueous systems;
Compounds X cyclization under acid effect becomes compounds X I and compounds X IV, and this reaction acid reagent adopts tosic acid, thionamic acid, camphorsulfonic acid, hydrochloric acid or sulfuric acid, and solvent is methylene dichloride;
The hydroxyl that compounds X I or compounds X IV is exposed is removed by Barton-McCombie reaction; The catalyzer of this reaction is imidazoles, solvent is tetrahydrofuran (THF), compounds X I or compounds X IV and sodium hydride, dithiocarbonic anhydride becomes xanthate with iodomethane reaction, separation and purification obtains compounds X II or compounds X V, is solvent at dioxane, and benzoyl peroxide is radical initiator, remove xanthate under triethyl silicane effect, obtain compounds X III or compounds X VI;
Compounds X III or compounds X VI removes benzyl under Lewis acid effect, obtains final product Pollen Brassicae campestris alkali A or Hyoscyamus niger L alkali B: this reaction adopts Lewis acid as benzyl oxide lytic reagent, and described Lewis acid adopts tin tetrachloride or titanium tetrachloride.
The analogue of Pollen Brassicae campestris alkali A and Hyoscyamus niger L alkali B a synthetic method, this employing Lewis acid is as benzyl oxide lytic reagent, and described Lewis acid adopts tin tetrachloride or titanium tetrachloride.
Total synthesis method of the present invention, adopts raw material cheap and easy to get, reaction solvent and reagent environmental pollution little, yield is high, and the alkaloid of synthesis and analogue may be used for development of new antiphlogiston Kangshuaining mixture.
Embodiment
Below in conjunction with embodiment, further detailed description is done to the present invention, but embodiments of the present invention are not limited thereto.
Weigh 15.19g sodium hydride and be placed in 500mL there-necked flask, dissolve with 50mLDMF, measure 10mL pyrroles, dissolve with 60mL DMF, the DMF solution (about 3 seconds one) of pyrroles is slowly dripped in flask under ice bath, drip off rear weighing 30.58g Compound II per, dissolve with 60mL DMF, (about 3 seconds one) stock liquid is slowly dripped in there-necked flask under ice bath, 1h is reacted under being transferred to 40 DEG C of oil baths, raise oil bath temperature to 135 DEG C, reaction 4-5 days, TLC (P:E=3:1) detection reaction completes substantially, add in a small amount of methyl alcohol and NaH, generate to bubble-free, underpressure distillation is except DMF, ethyl acetate is extractive reaction liquid repeatedly, organic phase is transferred to rotary evaporation in eggplant-shape bottle and removes most of solvent.Mix silica gel, obtain Tan solid powder, silica gel column chromatography, dry method loading, sherwood oil: ethyl acetate=8:1 wash-out, obtain white solid 16.18g (4), yield 70.9%.
Measure 80mL deionized water in 250mL there-necked flask, weigh 10.00g white K
2cO
3solid adds, add 50mL formaldehyde solution and 5g Compound II per after ultrasonic dissolution successively, be placed in microwave reactor, add reflux, stirring and refluxing reacts 2 hours 40 minutes, arranges reaction parameter to be: temperature of reaction 80 DEG C, 2 hours 40 minutes reaction times, reaction power 500W.Reaction solution is transferred in 250mL separating funnel, ethyl acetate 100mL × 3 extractive reaction liquid, anhydrous sodium sulfate drying organic layer.Suction filtration desalination, rotary evaporation removes desolventizing and obtains crude product 5.With in proper amount of acetone transfer crude product IV to 100mL Erlenmeyer flask, add 10-15g Manganse Dioxide, stirring at normal temperature reacts 2 days, suction filtration is except Manganse Dioxide, rotary evaporation filtrate removes desolventizing, silica gel column chromatography, sherwood oil: ethyl acetate=4:1 wash-out, obtain Tan solid 5.14g (V), two step total recoverys 87%.
1H NMR(400MHz,CDCl3)δ9.89(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 C
18H
24NO
7[M+H]
+366.1553,found366.1547.
54mL acetonitrile transfer 1g compound V to 100mL reaction flask, dissolve and stir, add 6mL deionized water and 124mg DDQ successively, reaction unit is transferred to back flow reaction 7h under 80 DEG C of oil baths, rotary evaporation goes out desolventizing, and 90mL acetic acid ethyl dissolution is transferred to 250mL separating funnel, and 2% sodium hydroxide solution washs 3 times, anhydrous sodium sulfate drying organic layer, suction filtration desalination.Rotary evaporation is except desolventizing, and silica gel column chromatography, sherwood oil: ethyl acetate=1:1, obtains product 756mg (VI), and yield is 85%.
1H NMR(400MHz,CDCl3)δ9.82(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 forC
15H
19NO
7Na[M+Na]
+348.1059,found 348.1058.
Methylene dichloride transfer 800mg raw material (VI) is to 100mL reaction flask, stirring and dissolving, add 159.2mg neopentyl glycol (NPG), ultrasonic dissolution, adds 50mg tosic acid, normal-temperature reaction 1h, add sodium bicarbonate neutralization, until bubble-free generates, suction filtration desalination, rotary evaporation is except desolventizing.Silica gel column chromatography, sherwood oil: ethyl acetate=1:1 wash-out, obtains 982mg white solid VII, and yield is 97%.
1H NMR(400MHz,CDCl
3)δ9.45(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 forC
20H
30NO
8[M+H]
+412.1971,found 412.1969.
900mg raw material (VII) is shifted to 100mL reaction flask with DMF, stirring and dissolving, add NaH (35%) 450mg, liquid-transfering gun is added dropwise to BnCl 600 μ L, normal-temperature reaction 3h, drips in number dropper methyl alcohol and NaH, until bubble-free generates, rotary evaporation desolventizes, 100mL ethyl acetate is transferred to 250mL separating funnel, 80mL × 3 water washing, anhydrous sodium sulfate drying organic layer, suction filtration desalination, rotary evaporation removes desolventizing, silica gel column chromatography, sherwood oil: ethyl acetate=4:1, obtain 1.138g white solid VIII, yield 88%.
1H NMR(400MHz,CDCl
3)δ9.49(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 C
34H
42NO
8[M+H]
+592.2910,found 592.2914.
Preparation deionized water: acetic acid=1:1 is 60mL solvent altogether, transfer 1g raw material (VIII) is to 100mL reaction flask, stirring and dissolving, back flow reaction 2 days under 100 DEG C of oil baths, rotary evaporation removes desolventizing, silica gel column chromatography, sherwood oil: ethyl acetate=1:1 wash-out, obtain colorless oil 728mg (IX), yield 92.5%.
1H NMR(400MHz,CDCl
3)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 C
26H
28NO
7[M+H]
+466.1866,found466.1872.
10mL methyl alcohol transferase 45 00mg Compound I X to 100mL reaction flask, adds 10.2mg NaBH in batches
4(96%), stirring and dissolving, reacts 30min under ice bath, and 30mL deionized water dissolving is transferred to 100mL separating funnel, 30mL × 3 dichloromethane extraction, organic phase anhydrous sodium sulfate drying, suction filtration desalination, rotary evaporation is except desolventizing, silica gel column chromatography, sherwood oil: ethyl acetate=1:1 washing, obtains colorless oil as product 450mg (X), yield 90%.
Methylene dichloride transfer 400mg compounds X is to 100mL reaction flask, 5mg tosic acid stirring and dissolving is added under ice bath, 10h is reacted under ice bath, add in appropriate saturated sodium bicarbonate solution and PTSA, until generate without gas is full, 30mL deionized water dissolving is transferred to 100mL separating funnel, 30mL × 3 dichloromethane extraction, organic phase anhydrous sodium sulfate drying, suction filtration desalination, rotary evaporation removes desolventizing, sherwood oil: ethyl acetate=3:1 wash-out, obtain white solid XI and XIV and be respectively 84mg, 256mg, yield 22% and 67%.
1H NMR(400MHz,CDCl
3)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,CDCl
3)δ178.8,137.9,137.9,135.1,131.3,128.9,128.5,128.45,127.9,127.8,127.8,124.4,104.8,96.9,77.33,76.7,72.3,71.6,71.5,71.3,65.6,61.6,58.4,29.7.HRMS(ESI)calcd for C
26H
28NO
6[M+H]
+450.1917,found450.1908.
200mg XI is dissolved in anhydrous tetrahydro furan, stirs under ice bath, add 5mg imidazoles and 73mg NaH, continue stirring 20 minutes, add 81 μ L CS2, continue to stir, add 50 μ L CH3I, continue reaction 30 minutes, add in methyl alcohol and NaH, ethyl acetate and moisture liquid, water layer extraction into ethyl acetate (3*50mL), merge organic layer, dry.Silica gel column chromatography is separated, sherwood oil: 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 C
28h
30nO
6s
2[M+H]
+100mg XII is dissolved in dry 5mL dioxane by 540.1515, found 540.1510., adds 148 μ L triethyl silicanes, is warming up to 90 DEG C, drips the dioxane solution of 45mg benzoyl peroxide.Be warming up to 100 DEG C of reactions 2 hours, be cooled to room temperature.Add the stirring of the 8%NaOH aqueous solution to spend the night.Ethyl acetate and moisture liquid, water layer extraction into ethyl acetate (3*50mL), merges organic layer, dry.Silica gel column chromatography is separated, sherwood oil: ethyl acetate=4:1 washing, obtains colorless oil as product XIII (46mg, 72%).
1H NMR(400MHz,CDCl
3)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).δC(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 forC
19H
22NO
5[M+H]
+344.1498,found 344.1494.
50mg XIII is dissolved in CH
2cl
2cryosel bath is cooled to-10 DEG C.Add 25 μ L TiCl
4, continue stirring 2 hours.Add saturated Na
2cO
3the aqueous solution, diatomite drainage desalination, extraction into ethyl acetate (3 × 20mL), anhydrous sodium sulfate drying, silica gel column chromatography is separated, sherwood oil: ethyl acetate=1:10 washing, obtains white solid Pollen Brassicae campestris alkali A (32mg, 87%).
1H NMR(400MHz,CDCl
3)δ9.46(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 forC
12H
16NO
5[M+H]
+254.1028,found 254.1024。
Claims (2)
1. a total synthesis method of Pollen Brassicae campestris alkali A and Hyoscyamus niger L alkali B, its feature comprises the steps.
1) with leavings group to 2,3; The hydroxyl that 4,5-diacetone fructose is exposed carries out esterification and obtains Compound II per, and Compound II per is p-toluenesulfonic esters, imidazole sulfonic acid ester or methanesulfonates;
2), under alkaline condition, Compound II per and pyrroles carry out nucleophilic substitution reaction and obtain compound III; Solvent is DMF or toluene, and alkaline condition is provided by NaH, KOH or NaOH, and temperature is 100-150 DEG C;
3) compound III is in formaldehyde solution, two methylolation obtains compound IV, and temperature is 20-120 DEG C, and solvent is water, ethanol, the one of methyl alcohol or mixed solvent, methylolation reagent is paraformaldehyde or formalin solution, and alkali is salt of wormwood, sodium carbonate or calcium carbonate;
4) the two hydroxyl oxidize of compound IV obtains two formyl adduct V; Organic solvent is acetone, ethyl acetate or DMSO, and oxygenant is Manganse Dioxide, the oxide compound of chromium or periodate oxidation thing, and temperature is 20-50 DEG C;
5) compound V is through selectivity deprotection, adopt following in one:
A, select protonic acid, collocation solvent is one in methyl alcohol, ethanol or mixed solvent, and temperature is ice bath or room temperature, obtains compound VI;
B, select Lewis acid, collocation solvent is one in methyl alcohol, ethanol or mixed solvent, and temperature is ice bath or room temperature, obtains compound VI;
C, select DDQ, solvent is acetonitrile and water, and temperature is 20-120 DEG C, obtains compound VI;
6) compound VI neopentyl glycol is protected aldehyde radical, obtains compound VI I, and reaction solvent is methylene dichloride, and catalysis adopts tosic acid, sulfuric acid or hydrochloric acid, room temperature or ice bath;
7) carry out benzyl protection to two hydroxyls of compound VI I, solvent is DMF, methylene dichloride, and benzylating reagent is BnCl or BnBr, and temperature is 20-60 DEG C, obtains compound VI II;
8) compound VI II is under sour water effect, remove isopropyl subunit protection and neopentyl glycol protection obtain Compound I X, in aqueous acetic acid backflow or employing trifluoroacetic acid and water stir at normal temperatures;
9) Compound I X adopts one of them aldehyde radical of sodium borohydride reduction to become hydroxyl to obtain compounds X, and reductive agent adopts sodium borohydride, lithium aluminum hydride or sodium triacetoxy borohydride, in methyl alcohol, ethanol or tetrahydrofuran (THF)/aqueous systems;
10) compounds X cyclization under acid effect becomes XI and XIV, and acid reagent adopts tosic acid, thionamic acid, camphorsulfonic acid, hydrochloric acid or sulfuric acid, and solvent is methylene dichloride;
11) hydroxyl that compounds X I or compounds X IV is exposed is removed by Barton-McCombie reaction, catalyzer is imidazoles, solvent is tetrahydrofuran (THF), with sodium hydride, dithiocarbonic anhydride becomes xanthate with iodomethane reaction, and separation and purification obtains XII or XV, be solvent at dioxane, benzoyl peroxide is radical initiator, removes xanthate under triethyl silicane effect, obtains compounds X III or XVI;
12) XIII or XVI removes benzyl under Lewis acid effect, obtains final product Pollen Brassicae campestris alkali A or Hyoscyamus niger L alkali B; Lewis acid is as benzyl oxide lytic reagent.
2. a synthetic method for the analogue of Pollen Brassicae campestris alkali A and Hyoscyamus niger L alkali B, its feature comprises the steps:
described Lewis acid adopts tin tetrachloride or titanium tetrachloride.
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