CN103265608A - Solanidine type glycoalkaloid and convergent synthesis method thereof - Google Patents
Solanidine type glycoalkaloid and convergent synthesis method thereof Download PDFInfo
- Publication number
- CN103265608A CN103265608A CN201310182368XA CN201310182368A CN103265608A CN 103265608 A CN103265608 A CN 103265608A CN 201310182368X A CN201310182368X A CN 201310182368XA CN 201310182368 A CN201310182368 A CN 201310182368A CN 103265608 A CN103265608 A CN 103265608A
- Authority
- CN
- China
- Prior art keywords
- rhap
- glcp
- compound
- acid
- solanidane
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to a solanidine type glycoalkaloid (I) and a convergent synthesis method thereof. The method comprises the following steps of: converting a compound (II) into a compound (III) through functional group conversion and protective group operation, removing acetyl, oxidizing to obtain a ketone compound (IV), then removing R2 and R3 protective groups, and performing a reductive amination reaction to obtain solanidine type sapogenin (V); and reacting an acyl-protected oligo-trichloroimido ester donor with a compound (V) under the glycosylation condition, and then removing the acyl protective group to obtain the solanidine type glycoalkaloid (I), wherein, R1 is an oligosaccharide chain of which the polymerization degree is 2 to 8; R2 is acyl or silicon group; R3 is alkoxycarbonyl; and R4 is an acyl-protected R1 oligosaccharide chain. The compounds have strong anti-tumor activity, and can be used for preparing anti-tumor medicaments.
Description
Technical field
The invention belongs to the synthetic field of medicine, relate to a kind of solanidane type glycoalkaloid and convergence type chemical synthesis process thereof.
Technical background
Solanidane type glycoalkaloid is the important Secondary Metabolism of Plant product of a class, mainly is distributed in the plant such as black nightshade, eggplant, tomato and potato etc. that the Solanum of Solanaceae and tomato belong to, by aglycon be connected in its sugar chain of 3 usually and form.Solanidane Alkaloid aglycon such as solanidane (solanidine), the general constructional feature for Buddhist nun's pyridine (leptinidine) and demissidine alkane (demissidine) etc. of Lay are that E ring and F ring form indoles connection pyridine ring (indolizidine), and 3 common sugar chain has chacotriose base (chacotriosyl), solatriose base (solatriosyl) and lycotetraose base (Lycotetraosyl).((α-chaconine), demissine (demissidine), leptine (leptine), leptinine (leptinine) and commersonine (commersonine) etc. are typical case's representative (Lee, the K.-R. of solanidane type glycoalkaloid to α-solanine for α-solanine), α-chaconine; Kozukue, N.; Han, J.-S.; Park, J.-H.; Chang, E.-Y.; Baek, E.-J.; Friedman, M.J.Agric.Food Chem.2004,52,2832-2839).
Solanidane type glycoalkaloid has antitumor, antiviral isoreactivity, and for example: α-chaconine has than anticancer drugs, doxorubicin (doxorubicin) and the higher activity of camptothecine (camptothecin) liver cancer cell.Studies show that in addition, in 0.1～10 μ g/ml concentration range, α-chaconine is than α-more effective inhibition HeLa Cells of solanine energy, liver cancer HepG2 cell, lymphatic cancer U937 cell, cancer of the stomach AGS and KATO III cell, and they are to slow [(a) Friedman, the M. of Normocellular breakdown speed comparison liver cancer cell; Lee, K.-R.; Kim, H.J.; Lee, I.S.; Kozukue, N.J.Agric.Food Chem.2005,53,6162-6169; (b) Friedman, M.; Levin, C.E.; Lee, S.-U.; Kim, H.-J.; Lee, I.S.; Byun, J.-O.; Kozukue, N.J.Agric.Food Chem.2009,57,5727-5733].α-chaconine and α-solanine can also suppress leaf spot of Chinese cabbage bacterium and purple blotch of onion bacterium (Zhao Xuesong, height is listened, Wang Juan, Xu Wenjing, the Zhou Yifa research and development of natural products, 2009,21,36-43).These studies show that solanidane type glycoalkaloid has as the good speciality of medicament research and development symptom of a trend compound.
Solanidane type glycoalkaloid mainly obtains by the degraded of separation and Extraction or natural product at present.The synthetic method of relevant solanidane type sapogenin and glucosides thereof is also few.Uhle group (Uhle, F.C.; Sallmann, F.J.Am.Chem.Soc.1960,82,1190-1199) with Sato group (Sato, Y.; Latham, JR., H.G.; Mosettig, E.J.Org.Chem.1957,22,1496-1500) utilize convallagenin and solasodine to synthesize 25S respectively, 22 uncertain solanidine analogues of three-dimensional arrangement; Utilize the Koenigs-Knorr method, Schreiber synthesized solanidine monoglycosides (Schreiber, K.Angew.Chem.1955,67,127-128).
Summary of the invention
It is the synthetic solanidane type glycoalkaloid of raw material to body that one of purpose of the present invention provides with solanidane type sapogenin and multiple oligosaccharides three chlorimide esters.
Another object of the present invention provides a kind of succinct, efficient, convergence type synthetic method that stereoselectivity prepares above-mentioned solanidane type glycoalkaloid.
The structure of solanidane type glycoalkaloid of the present invention is as shown in the formula shown in (I):
Wherein,
Dotted line represents between 5,6 it is singly-bound or two key (Δ
5), and it is when being singly-bound, 5 hydrogen atoms are α or beta comfiguration;
The absolute configuration of 22 carbon is R or S;
The absolute configuration of 25 carbon is R or S;
R
1Be by β-D-Glucopyranose (β-D-Glcp), β-D-galactopyranose (β-D-Galp), β-D-mannopyranose (β-D-Manp), α-D-mannopyranose (α-D-Manp), β-L-mannopyranose (β-L-Manp), α-L-mannopyranose (α-L-Manp), β-D-xylopyranose (β-D-Xylp), β-D-pyrans glucosamine (β-D-GlcNACp), α-L-pyrans rhamnosyl (α-L-Rhap), α-D-pyrans rhamnosyl (α-D-Rhap), β-D-pyrans/furans pectinose (β-D-Araf/p), α-D-pyrans/furans pectinose (α-D-Araf/p), α-L-pyrans/furans pectinose (α-L-Araf/p), β-L-pyrans/furans pectinose (β-L-Araf/p), α-L-pyrans Fucose (β-D-Fucp), beta d glucopyranosiduronic acid (β-D-GlcAp), (β-D-GalAp) polymerization degree of composition such as monose such as grade is the chain of 2-8 or the oligosaccharides of ramiform to β-D-galactopyranose aldehydic acid;
Wherein preferably:
α-L-Rhap-(1→4)-[α-L-Rhap-(1→2)]-β-D-Glcp；
β-D-Glcp-(1→3)-[α-L-Rhap-(1→2)]-β-D-Galp；
α-L-Araf-(1→4)-[α-L-Rhap-(1→2)]-β-D-Glcp；
α-L-Arap-(1→4)-[α-L-Rhap-(1→2)]-β-D-Glcp；
β-D-Xylp-(1→4)-[α-L-Rhap-(1→2)]-β-D-Glcp；
α-D-Manp-(1→4)-[α-D-Manp-(1→2)]-β-D-Glcp；
α-D-Rhap-(1→4)-[α-D-Rhap-(1→2)]-β-D-Glcp；
α-L-Manp-(1→4)-[α-L-Manp-(1→2)]-β-D-Glcp；
{α-L-[α-L-Rhap-(1→4)]-Rhap-(1→4)}-[α-L-Rhap-(1→2)]-β-D-Glcp；
{α-L-[β-D-Xylp-(1→4)]-Rhap-(1→4)}-[α-L-Rhap-(1→2)]-β-D-Glcp；
{α-L-[β-D-Xylp-(1→3)]-Rhap-(1→2)}-β-D-Glcp-(1→4)}-β-D-Galp;
α-L-Rhap-(1→2)-β-D-Glcp；α-D-Manp-(1→2)-β-D-Glcp；
α-D-Rhap-(1→2)-β-D-Glcp；α-L-Manp-(1→2)-β-D-Glcp；
The convergence type synthetic method of above-mentioned solanidane type glycoalkaloid is characterized in that this method comprises the steps:
Be raw material (Chinese invention patent with compound (II); application number: 201310126415.9) be converted into compound (III) through functional group's conversion and protecting group operation; then obtain ketone compounds (IV) through deacetylation and oxidation; and then the protecting group and the reductive amination process that remove amino and hydroxyl obtain solanidane type sapogenin (V); under certain glucosides condition; compound (IV) obtains corresponding glucosides (VI) with the oligosaccharides three chlorimide esters of acyl group protection to precursor reactant, removes the acyl group protecting group then and gets solanidane type glycoalkaloid (I).
Concrete each step is as follows:
(1) preparation of compound (III):
In solvent, compound (II) (Chinese invention patent, application number: 201310126415.9) with reductive agent or catalytic hydrogenation reductive condition, under 1-100 air pressure, in 0-100 ℃ nitrine is converted into amino, and carry out reductive amination process with 22 carbonyls, get compound (III), wherein R with the earbalkoxylation reagent react then
2Be silica-based or the acyl group protecting group, R
3It is the carbalkoxy protecting group.
Described solvent is C
1-C
6Single halo or many halogenated alkanes, 1,4 – dioxane, ether, acetonitrile, 2,2,2 – trimethylacetonitriles, acetonitrile, tetrahydrofuran (THF), N, N – dimethyl formamide, N, C such as N – N,N-DIMETHYLACETAMIDE, hexamethylphosphoramide, N-methylpyrrolidin-2-ketone, toluene, phenylfluoroform, pyridine, methyl alcohol, ethanol, Virahol
1-C
6Alkyl alcohols, water in a kind of or their mixture.
Preferred solvent is C such as methyl alcohol, ethanol, Virahol
1-C
6Alkyl alcohols, water in a kind of or their mixture.
Described acyl group is C
2-C
6Straight or branched aliphatic acyl radical or C
6-C
10Aromaticacyl radical.
Preferred acyl group is ethanoyl, chloracetyl, pivaloyl group, 4-carbonyl pentanoyl, 2-chloro-2-methyl-propionyl, benzoyl, adjacent azido-methyl benzoyl, 2-(2-nitrophenyl)-ethanoyl, tribromo-acetyl base;
Described silica-based be methyl, ethyl, sec.-propyl, the tertiary butyl, phenyl etc. constitute three replace silica-based.
Preferred silica-based is that tertiary butyl dimethyl is silica-based, tert-butyl diphenyl is silica-based.
Described reductive agent is metal borohydride and benzenethiols, 1 such as the trivalent phosphine compound that constitutes such as methyl, ethyl, sec.-propyl, the tertiary butyl, phenyl and sodium borohydride, lithium borohydride, zinc borohydride, hydroboration calcium, POTASSIUM BOROHYDRIDE, sodium cyanoborohydride, mercaptan compounds such as 3-dimercaptopropane; The mol ratio of reductive agent and compound (I) is (0.1-10.0): 1.0.
Described catalytic hydrogenation reductive condition is by 5-10%Pd/C, 20%Pd (OH)
2/ C, Lindlar catalyzer or Raney-Ni and H
2Or ammonium formiate is formed; The mass ratio of the catalyzer that catalytic hydrogenation is required and compound (I) is (0.1-100.0): 1.0.
Described carbalkoxy is carbobenzoxy-(Cbz) (Cbz), tertbutyloxycarbonyl (Boc), allyloxycarbonyl (Alloc), 2,2,2-trichloro-ethoxycarbonyl (Troc), 9-fluorenylmethyloxycarbonyl (Fmoc).
The muriate that described earbalkoxylation reagent is carbalkoxy or its N-hydroxy-succinamide ester; The mol ratio of earbalkoxylation reagent and compound (I) is (0.1-10.0): 1.0.
(2) preparation of compound (IV):
In the presence of alkali, in solvent, under 0-100 ℃ of condition, remove in the compound (III) 16 ethanoyl, then get compound (IV) with oxygenant oxidation alcoholic extract hydroxyl group; The mol ratio of alkali and compound (III) is (0.1-5.0): 1.0; Oxygenant is (0.1-10.0) with the mol ratio of alcohol: 1.0.
Described alkali can be mineral alkali, a kind of as in sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, yellow soda ash, salt of wormwood, the cesium carbonate; Also can be organic bases such as potassium tert.-butoxide, sodium methylate, sodium ethylate, magnesium methylate, triethylamine, pyridine, 4-N, N-lutidine, 2, a kind of in 6-lutidine, 2, diisopropyl ethyl amine, the tetrabutyl ammonium fluoride.
Described solvent such as step (1).
Preferred solvent is C such as methyl alcohol, ethanol, Virahol
1-C
6Alkyl alcohols, C
1-C
6Single halo or many halogenated alkanes, ethyl acetate, dimethyl sulfoxide (DMSO), water or their mixture.
Described oxygenant is Dess-Martin oxygenant, IBX, dimethyl sulfoxide (DMSO)/oxalyl chloride, PDC, PCC, i-Pr
4NRuO
4/ TEMPO etc.
(3) preparation of compound (V):
Compound (IV) carries out reductive amination process with reductive agent or catalytic hydrogenation reductive condition in solvent in the presence of protonic acid or Lewis acid, remove its 3 protecting groups then and get compound (V).
Described Lewis acid or protonic acid are trimethylsilyl trifluoromethanesulfonates, the silica-based triflate of triethyl, the silica-based triflate of tertiary butyl dimethyl, boron trifluoride diethyl etherate, silver trifluoromethanesulfonate, copper trifluoromethanesulfcomposite, trifluoromethanesulfonic acid zinc, the trifluoromethanesulfonic acid scandium, the trifluoromethanesulfonic acid lanthanum, Ytterbiumtriflate, the trifluoromethanesulfonic acid indium, trifluoromethanesulfonic acid, or perchloric acid, Tetrafluoroboric acid, four (phenyl-pentafluoride base) boric acid, two (fluoroform sulphonyl) imines, trichoroacetic acid(TCA), trifluoroacetic acid, formic acid, acetic acid, SiO
2-H
2SO
4, SiO
2-HClO
4, SiO
2A kind of among the-HOTf or their mixture.
Described reductive agent or catalytic reduction condition such as step (1).
(4) preparation of compound (VI):
In solvent and dewatering agent in the presence of, in-78-40 ℃, be promotor with Lewis acid or protonic acid, compound (V) is given precursor reactant 1-48 hour with the oligosaccharides three chlorimide esters of acyl group protection, gets the solanidane class glycoalkaloid (VI) of protection; R wherein
4Be the R of acyl group protection
1Oligonucleotide chain; Compound (V) is 1.0:(1.0-5.0 with the mol ratio of glycosyl donor and promotor): (0.05-3.0); The weight ratio 1.0:(3.0-10.0 of compound (V) and dewatering agent).
Described solvent such as step (1).
Preferred solvent is CH
2Cl
2, CHCl
3, ClCH
2CH
2Cl, 2,2, the mixed solvent of a kind of or their two or more different ratioss in 2-trimethylacetonitrile, the phenylfluoroform.
Described Lewis acid or protonic acid step (3).
Preferred Louis acid or protonic acid be trimethylsilyl trifluoromethanesulfonate,, the silica-based triflate of tertiary butyl dimethyl, boron trifluoride diethyl etherate, silver trifluoromethanesulfonate, trifluoromethanesulfonic acid zinc, trifluoromethanesulfonic acid scandium, trifluoromethanesulfonic acid lanthanum, perchloric acid, Tetrafluoroboric acid, four (phenyl-pentafluoride base) boric acid, two (fluoroform sulphonyl) imines, SiO
2-H
2SO
4, SiO
2-HClO
4, SiO
2A kind of among the-HOTf or their mixture.
Described dewatering agent is
A kind of in molecular sieve or AW-300 molecular sieve or anhydrous sodium sulphate, anhydrous calciumsulphate, anhydrous cupric sulfate, the anhydrous magnesium sulfate or their mixture.
Described oligosaccharides such as R
1
Described acyl group such as step (1).
(5) preparation of compound (I):
In solvent, at-78-180 ℃, remove the acyl group protecting group of solanidane class glycoalkaloid (VI) with alkali, get solanidane class glycoalkaloid (I); Wherein the mol ratio of alkali and compound (VI) is (0.1 – 100.0): 1.0.
Described alkali such as step (2).
Described solvent such as step (1).
Preferred solvent is C such as methyl alcohol, ethanol, Virahol
1-C
6Alkyl alcohols, water or their mixture.
Method of the present invention is preferably carried out under protection of inert gas, as argon gas, nitrogen etc.
The invention provides a kind of easy, solanidane type glycoalkaloid convergence type synthetic method efficiently, a kind of preparation method of simple, practical solanidane type sapogenin also is provided simultaneously.
The prepared solanidane type glycoalkaloid of the present invention has stronger anti-tumor activity, can be used for preparing anti-tumor medicine.
Description of drawings
Fig. 1 is 25(R)-the synthesis step figure of solanidine.
Reagent and condition: Lindlar.cat (a) i), H
2, ethanol, THF, r.t, 5h; Ii) NaBH
3CN, HOAc, methanol, THF, r.t, overnight, 81%for two steps.(b)i)(Boc)
2O,NaHCO
3,Dioxone,H
2O,r.t～40℃,26h,91%；ii)K
2CO
3,CH
3OH,THF,70℃,20h,87%。(c)i)PDC,CH
2Cl
2,r.t,4h,96%；ii)TFA,CH
2Cl
2,5%H
2O,r.t,1h；iii)NaBH
3CN,HOAc,CH
3OH,r.t,overnight；iv)1M?NaOH,CH
3OH,65℃reflux,10h,92%over?three?steps。
Fig. 2 is 25(R)-the synthesis step figure of solanine.
Reagent and condition: (a) HB (C
6F
5)
4, BTF, t-BuCN, CH
2Cl
2,
-20 ℃, 4h, 98%; (b) CH
3OH, 1NNaOH, 70 ℃, 9h, 86%.
Embodiment
Below in conjunction with accompanying drawing, with synthesizing as specific embodiment of 25 (R)-solanidines and 25 (R)-solanines, the present invention is described in detail, but the invention is not restricted to following content.
(1) preparation of compound 2 and data
Take by weighing compound 1 (1.0g; 1.36mmol) (Chinese invention patent; application number: 201310126415.9) in the single port bottle that magnetic agitation is housed; add anhydrous tetrahydro furan (40mL) successively; dehydrated alcohol (40mL) sample dissolution adds Lindlar catalyzer (400mg) again, hydrogen ventilation three times; under 1atm, react 5h; suction filtration concentrates, and adds anhydrous tetrahydro furan (20mL) successively in enriched material, anhydrous methanol (20mL) sample dissolution; add Glacial acetic acid (570uL; 9.49mmol), sodium cyanoborohydride (436mg, 6.78mmol); the stirring at room reaction was regulated pH value to 10, concentrating under reduced pressure with the 1M aqueous sodium hydroxide solution after 16 hours under the argon shield.The gained resistates dilutes with methylene dichloride, and distilled water wash is collected organic phase and used anhydrous sodium sulfate drying, and suction filtration concentrates, column chromatography (CH
2Cl
2: MeOH:Et
3N=150:1:0.15), collect to concentrate compound 2a (765mg, 81%), be directly used in next step reaction without sign.
Take by weighing previous step gained compound 2a (100mg 0.14mmol) in the single port bottle that magnetic agitation is housed, adds 1,4-dioxane (2mL) successively, distilled water (0.2mL) sample dissolution, add then sodium bicarbonate (121mg, 1.44mmol) and (Boc)
2O (157mg, 0.27mmol).After the stirring at room reaction is spent the night temperature of reaction is risen to 40 ℃, continue reaction 12h.Reaction solution dilutes with methylene dichloride, uses distilled water, saturated common salt water washing successively, collects organic phase.Through anhydrous sodium sulfate drying, filtration, filtrate concentrate back column chromatography (petroleum ether:AcOEt=8:1), get compound 2 (104mg, 91%).Its data are as follows:
1H?NMR(600MHz,CDCl
3)δ7.66(m,4H),7.40(m,6H),5.37(m,1H),5.10(d,1H,J=4.8Hz),3.87(s,1H),3.72(d,1H,J=13.7Hz,),3.50(m,1H),2.93(dd,1H,J=14.0,5.1Hz),2.01(s,3H),1.44(s,9H),1.05(s,9H),0.98(m,6H),0.94(d,3H,J=6.6Hz),0.87(s,3H)；
13C?NMR(126MHz,CDCl
3)δ170.7,157.1,141.4,135.87,135.86,134.9,134.8,129.58,129.55,127.58,127.55,121.0,79.2,77.4,73.3,56.7,55.5,55.2,50.0,45.3,42.9,42.6,39.8,37.2,36.5,35.2,35.1,31.9,31.7,31.4,28.9,28.7,27.3,27.1,25.0,21.6,20.7,19.8,19.5,19.3,14.1,13.1；
MS(ESI)m/z796.5[M+H]
+；
HRMS-ESI?TOF:m/z[M+H]
+calcd?for?C
50H
74O
5NSi:796.5331;found:796.5327。
(2) preparation of compound 3 and data
Take by weighing compound 2 (73mg, 0.092mmol), Anhydrous potassium carbonate (38mg, 0.28mmol) in the single port bottle that magnetic agitation is housed, add anhydrous tetrahydro furan (2mL) successively, anhydrous methanol (4mL) sample dissolution placed 70 ℃ of oil bath back flow reaction 20 hours then.Solids removed by filtration, filtrate be column chromatography (petroleum ether:AcOEt=10:1) behind concentrating under reduced pressure, gets compound 3 (60mg, 87%).Its data are as follows:
1H?NMR(600MHz,CDCl
3)δ7.68(m,4H),7.36(m,6H),5.12(d,1H,J=5.2Hz),4.49(dd,1H,J=11.4,6.7Hz),4.01(dd,1H,J=11.1,8.1Hz),3.69(d,1H,J=13.1Hz),3.52(m,1H),3.02(dd,1H,J=13.9,5.0Hz,),1.45(m,9H),1.06(s,9H),1.00(d,3H,J=7.1Hz),0.99(s,3H),0.95(d,3H,J=6.6Hz),0.89(s,3H)；
13C?NMR(151MHz,CDCl
3)δ157.4,141.5,135.9,134.92,134.88,129.6,129.5,127.57,127.55,79.2,73.3,57.8,57.0,54.9,50.1,42.62,42.56,40.0,37.3,37.0,36.6,34.7,32.0,31.8,31.5,29.1,28.6,27.9,27.1,24.1,20.7,20.2,19.5,19.2,15.1,13.5；
MS(ESI)m/z754.59[M+H]
+；
HRMS-ESI?TOF:m/z[M+H]
+calcd?for?C
45H
72O
4NSi:754.5225;found:754.5217。
(3) preparation of compound 5 and data
Take by weighing compound 3(457mg, 0.61mmol), add anhydrous methylene chloride (15mL) sample dissolution, adding PDC (342mg, 0.91mmol), behind the room temperature reaction 2h, concentrating under reduced pressure, then column chromatography (petroleum ether:AcOEt=10:1) white solid (437mg, 0.58mmol), yield 96%.
Take by weighing the oxidation products (150mg of previous step reaction gained, 0.20mmol) in the single port bottle that magnetic agitation is housed, add methylene dichloride (2.4mL), trifluoracetic acid (1.2mL), distilled water (180uL) successively, behind the room temperature reaction 1 hour, concentrating under reduced pressure gained resistates is dissolved in the methyl alcohol (7.0mL), add acetic acid (171uL then, 3.0mmol) and sodium cyanoborohydride (125mg, 2.0mmol), after room temperature reaction spends the night, reaction solution gets compound 5(73mg, 0.18mmol, 92% through the concentrating under reduced pressure column chromatography).Its data are as follows:
1H?NMR(600MHz,CDCl
3)δ5.32(d,1H,J=4.9Hz),3.59(dd,1H,J=17.5,7.6Hz),3.47(m,1H),2.83–2.74(m,2H),2.29–2.17(m,5H),2.00–1.93(m,1H),1.00(s,3H),0.86(t,3H,J=7.0Hz),0.83(s,3H),0.77(d,3H,J=6.5Hz)；
13C?NMR(151MHz,CDCl
3)δ141.1,121.5,71.7,66.5,64.4,61.3,56.6,55.2,50.3,42.4,40.9,40.6,37.4,36.8,34.8,33.5,32.3,31.8,31.2,30.2,25.7,23.8,21.1,19.7,19.5,16.4,16.1；
MS(ESI)m/z398.2[M+H]
+；
HRMS-ESI?TOF:m/z[M+H]
+calcd?for?C
27H
44ON:398.3417;found:398.3406。
(4) preparation of compound 7 and data
(30mg is 0.075mmol) in new activation is housed to take by weighing compound 5
In the tube sealing of molecular sieve and magnetic agitation, add phenylfluoroform (1.5mL), tertiary butyl acetonitrile (0.3mL), methylene dichloride (0.5mL) successively, after 20 minutes, add HB (C-20 ℃ of stirrings again
6F
5)
4Dichloromethane solution, in 3.5 hours, slowly add compound 6 (159mg, dichloromethane solution 0.12mmol) (1.5mL); Continuation was stirred after 12 hours, with triethylamine cancellation reaction, and filtration, concentrated, column chromatography (CH
2Cl
2: MeOH=200:1) get compound 7 (108mg, 92%).Its data are as follows:
1H?NMR(600MHz,CDCl
3)δ8.03(m,4H),7.92(m,3H),7.80(m,4H),7.51(m,J=4H),7.39(q,5H,J=7.9Hz),7.34(t,4H,J=7.8Hz),7.27–7.23(m,1H),6.01(t,1H,J=9.7Hz),5.66(t,1H,J=9.7Hz),5.44(d,1H,J=3.8Hz),5.40(dd,1H,J=9.9,7.7Hz),5.28–5.25(m,3H),5.16(d,1H,J=7.7Hz),5.08(s,1H),5.04(m,1H),4.63(dd,1H,J=12.2,5.4Hz),4.57(dd,1H,J=12.0,3.2Hz),4.44(dd,1H,J=11.3,7.6Hz),4.32–4.28(m,2H),4.24–4.18(m,2H),4.02(m,2H),3.81(m,1H),3.73(m,1H),3.54(m,1H),3.48(m,1H),3.10(m,1H),2.67(m,1H),2.54(m,1H),2.38(m,1H),2.22(m,1H),2.13(s,3H),2.07(s,3H),2.00(s,3H),1.77(s,3H),1.06(d,3H,J=6.2Hz),1.00(d,3H,J=6.8Hz),0.93(s,3H),0.92(d,3H,J=6.1Hz),0.87(s,3H)；
13C?NMR(126MHz,CDCl
3)δ170.4,170.3,170.0,166.2,166.1,165.6,165.3,165.2,140.5,133.5,133.2,133.2,130.03,129.98,129.9,129.83,129.81,129.76,129.4,129.1,129.0,128.6,128.50,128.48,128.4,128.3,121.5,110.1,100.2,99.4,97.2,77.0,74.3,72.9,72.7,72.5,71.2,71.08,70.13,70.05,69.5,69.1,66.6,64.9,62.9,62.5,49.9,41.1,40.2,38.5,37.0,36.9,34.9,33.9,32.10,32.05,31.0,29.8,29.6,29.5,29.3,29.1,23.1,22.8,20.9420.9,20.8,19.3,19.0,17.3,16.0,14.2；
MS(ESI)m/z1556.7[M+H]
+；
HRMS-ESI?TOF:m/z[M+H]
+calcd?for?C
88H
102O
24N:1556.6786;found:1556.6787。
(5) preparation of compound 8 and data
(69mg 0.044mmol) in the single port bottle that magnetic agitation is housed, adds methyl alcohol (4mL) sample dissolution, and the 1M aqueous sodium hydroxide solution is regulated pH to 12, places 70 ℃ of oil bath back flow reaction after 9 hours, concentrating under reduced pressure, column chromatography (CH to take by weighing compound 7
2Cl
2: MeOH contains 8% water=5:1+0.1%Et
3N=7:1～5:1～3:1) must product 8 (33mg, 86%).Its data are as follows:
1H?NMR(600MHz,pyridine-d
5)δ6.29(s,1H),5.38(d,1H,J=4.5Hz),5.19(d,1H,J=7.7Hz),4.96–4.88(m,4H),4.81(d,1H,J=2.3Hz),4.70(t,1H,J=8.9Hz),4.61(dd,1H,J=9.2,3.1Hz),4.47(d,1H,J=10.0Hz),4.39(dd,1H,J=11.2,6.5Hz,),4.35–4.15(m,6H),4.06–3.89(m,4H),3.60(1H,m),2.89(d,1H,J=11.8Hz),2.79(dt,3H,J=23.5,10.8Hz),2.33–2.21(m,2H),2.13(d,1H,J=11.2Hz),2.06–1.98(m,1H),1.89(dd,1H,J=23.9,10.8Hz),1.70(d,3H,J=6.2Hz),1.08(s,3H),0.91(d,3H,J=7.0Hz),0.88(s,3H),0.78(d,2H,J=6.3Hz)；
13C?NMR(126MHz,pyridine-d
5)δ141.3,122.3,106.2,102.6,100.8,85.2,78.8,78.7,78.0,76.8,75.5,75.3,74.5,73.2,72.9,71.9,70.7,69.8,66.7,64.5,62.9,62.4,57.0,55.6,50.8,41.4,40.9,39.2,37.9,37.6,35.0,34.4,33.0,31.9,31.0,30.6,26.0,24.3,21.6,20.2,19.8,19.0,17.1,16.6；
MS(ESI)m/z868.5[M+H]
+；
HRMS-ESI?TOF:m/z[M+H]
+calcd?for?C
45H
74O
15N:868.5053;found:868.5065。
The above only is the specific embodiment of the present invention, but protection scope of the present invention is not limited thereto, and any variation or replacement of expecting without creative work all should be encompassed within protection scope of the present invention.Therefore, protection scope of the present invention should be as the criterion with the protection domain that claims were limited.
Claims (10)
1. solanidane type glycoalkaloid is characterized in that its general structure is as shown in the formula shown in (I):
Wherein,
Dotted line represents between 5,6 it is singly-bound or two key;
The absolute configuration of 22 carbon is R or S;
The absolute configuration of 25 carbon is R or S;
R
1Be that the polymerization degree is the chain of 2-8 or the oligosaccharides of ramiform.
2. solanidane type glycoalkaloid according to claim 1 is characterized in that described R
1Be by β-D-Glucopyranose, β-D-galactopyranose, β-D-mannopyranose, α-D-mannopyranose, β-L-mannopyranose, α-L-mannopyranose, β-D-xylopyranose, β-D-pyrans glucosamine, α-L-pyrans rhamnosyl, α-D-pyrans rhamnosyl, β-D-pyrans/furans pectinose, α-D-pyrans/furans pectinose, α-L-pyrans/furans pectinose, β-L-pyrans/furans pectinose, α-L-pyrans Fucose, beta d glucopyranosiduronic acid or β-D-galactopyranose aldehydic acid is formed.
3. solanidane type glycoalkaloid according to claim 1 and 2 is characterized in that described R
1A kind of in the following oligosaccharides preferably:
α-L-Rhap-(1→4)-[α-L-Rhap-(1→2)]-β-D-Glcp；
β-D-Glcp-(1→3)-[α-L-Rhap-(1→2)]-β-D-Galp；
α-L-Araf-(1→4)-[α-L-Rhap-(1→2)]-β-D-Glcp；
α-L-Arap-(1→4)-[α-L-Rhap-(1→2)]-β-D-Glcp；
β-D-Xylp-(1→4)-[α-L-Rhap-(1→2)]-β-D-Glcp；
α-D-Manp-(1→4)-[α-D-Manp-(1→2)]-β-D-Glcp；
α-D-Rhap-(1→4)-[α-D-Rhap-(1→2)]-β-D-Glcp；
α-L-Manp-(1→4)-[α-L-Manp-(1→2)]-β-D-Glcp；
{α-L-[α-L-Rhap-(1→4)]-Rhap-(1→4)}-[α-L-Rhap-(1→2)]-β-D-Glcp；
{α-L-[β-D-Xylp-(1→4)]-Rhap-(1→4)}-[α-L-Rhap-(1→2)]-β-D-Glcp；
{α-L-[β-D-Xylp-(1→3)]-Rhap-(1→2)}-β-D-Glcp-(1→4)}-β-D-Galp;
α-L-Rhap-(1→2)-β-D-Glcp；α-D-Manp-(1→2)-β-D-Glcp；
α-D-Rhap-(1→2)-β-D-Glcp；α-L-Manp-(1→2)-β-D-Glcp。
4. the convergence type synthetic method of a solanidane type glycoalkaloid as claimed in claim 1 is characterized in that this method
Comprise the steps:
(1) preparation of compound (III):
Change reaction, get with the earbalkoxylation reagent react then
Compound (III), wherein R
2Be silica-based or the acyl group protecting group, R
3It is the carbalkoxy protecting group;
(4) preparation of compound (VI):
Sapogenin (V) is 1.0:(1.0-5.0 with the mol ratio of glycosyl donor, promotor and dewatering agent): (0.05-3.0): (3.0-10.0);
(5) preparation of compound (I):
In solvent, at-78-180 ℃, remove the acyl group protecting group of the solanidane class glycoalkaloid (VI) of protection with alkali, get solanidane class glycoalkaloid (I); Wherein the mol ratio of alkali and compound (VI) is (0.1-100.0): 1.0;
Above-mentioned solvent is C
1-C
6Single halo or many halogenated alkanes, 1,4 – dioxane, ether, acetonitrile, 2,2,2 – trimethylacetonitriles, acetonitrile, tetrahydrofuran (THF), N, N – dimethyl formamide, N, N – N,N-DIMETHYLACETAMIDE, hexamethylphosphoramide, N-methylpyrrolidin-2-ketone, toluene, phenylfluoroform, pyridine, C
1-C
6Alkyl alcohols, a kind of or its mixture in the water.
5. synthetic method as claimed in claim 4 is characterized in that the acyl group described in the step (1) is C
2-C
6Straight or branched aliphatic acyl radical or C
6-C
10Aromaticacyl radical; Preferably ethanoyl, chloracetyl, tribromo-acetyl base, pivaloyl group, 4-carbonyl pentanoyl, 2-chloro-2-methyl-propionyl, benzoyl, adjacent azido-methyl benzoyl, 2-(2-nitrophenyl)-ethanoyl; Described silica-based be methyl, ethyl, sec.-propyl, the tertiary butyl, phenyl constitute three replace silica-based; Preferably tertiary butyl dimethyl is silica-based or tert-butyl diphenyl is silica-based.
6. synthetic method as claimed in claim 4 is characterized in that the reductive agent described in step (1) or (3) is the metal borohydride of one of the trivalent phosphine compound that constitutes of methyl, ethyl, sec.-propyl, the tertiary butyl, phenyl or sodium borohydride, lithium borohydride, zinc borohydride, hydroboration calcium, POTASSIUM BOROHYDRIDE, sodium cyanoborohydride; The catalytic hydrogenation reductive condition is 5-10%Pd/C, 20%Pd (OH)
2/ C, Lindlar catalyzer or Raney-Ni and H
2Or ammonium formiate.
7. synthetic method as claimed in claim 4 is characterized in that the carbalkoxy described in the step (1) is carbobenzoxy-(Cbz), tertbutyloxycarbonyl, allyloxycarbonyl, 2,2, a kind of in 2-trichloro-ethoxycarbonyl, the 9-fluorenylmethyloxycarbonyl; The muriate that described earbalkoxylation reagent is carbalkoxy or its N-hydroxy-succinamide ester.
8. synthetic method as claimed in claim 4 is characterized in that the Lewis acid described in step (3) or (4) or protonic acid are trimethylsilyl trifluoromethanesulfonates, the silica-based triflate of triethyl, the silica-based triflate of tertiary butyl dimethyl, boron trifluoride diethyl etherate, silver trifluoromethanesulfonate, copper trifluoromethanesulfcomposite, trifluoromethanesulfonic acid zinc, the trifluoromethanesulfonic acid scandium, the trifluoromethanesulfonic acid lanthanum, Ytterbiumtriflate, the trifluoromethanesulfonic acid indium, trifluoromethanesulfonic acid, or perchloric acid, Tetrafluoroboric acid, four (phenyl-pentafluoride base) boric acid, two (fluoroform sulphonyl) imines, trifluoroacetic acid, formic acid, acetic acid, SiO
2-H
2SO
4, SiO
2-HClO
4, SiO
2A kind of or its mixture among-the HOTf.
9. synthetic method as claimed in claim 4 is characterized in that the dewatering agent described in the step (4) is
A kind of or its mixture in molecular sieve or AW-300 molecular sieve or anhydrous sodium sulphate, anhydrous calciumsulphate, anhydrous cupric sulfate, the anhydrous magnesium sulfate.
10. synthetic method as claimed in claim 4, it is characterized in that the alkali described in step (2) or (5) is a kind of or potassium tert.-butoxide, sodium tert-butoxide, tert-butyl lithium, sodium methylate, sodium ethylate, magnesium methylate, pyridine, the 4-N in oxyhydroxide, hydride or the carbonate, N-lutidine, 2,6-lutidine, 2, a kind of in 4,6-trimethylpyridine, the tetrabutyl ammonium fluoride.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310182368.XA CN103265608B (en) | 2013-05-16 | 2013-05-16 | Solanidine type glycoalkaloid and convergent synthesis method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310182368.XA CN103265608B (en) | 2013-05-16 | 2013-05-16 | Solanidine type glycoalkaloid and convergent synthesis method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103265608A true CN103265608A (en) | 2013-08-28 |
| CN103265608B CN103265608B (en) | 2015-04-22 |
Family
ID=49009280
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310182368.XA Active CN103265608B (en) | 2013-05-16 | 2013-05-16 | Solanidine type glycoalkaloid and convergent synthesis method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103265608B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112094310A (en) * | 2020-09-01 | 2020-12-18 | 南京师范大学 | Glucosinolate sterol glycoside and glucosinolate stanol glycoside, and preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0020029A1 (en) * | 1979-05-02 | 1980-12-10 | Aruba (Qld.) Pty. Ltd. | Pharmaceutical compositions comprising steroid alkaloids |
-
2013
- 2013-05-16 CN CN201310182368.XA patent/CN103265608B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0020029A1 (en) * | 1979-05-02 | 1980-12-10 | Aruba (Qld.) Pty. Ltd. | Pharmaceutical compositions comprising steroid alkaloids |
Non-Patent Citations (4)
| Title |
|---|
| PHILIPPE RENAUD ET AL: "Concise Synthesis of Pyrrolidine and Indolizidine Alkaloids by a Highly Convergent Three-Component Reaction", 《CHEMISTRY-A EUROPEAN JOURNAL》, vol. 17, no. 11, 9 February 2011 (2011-02-09), pages 3209 - 3210 * |
| PHILIPPE RENAUD ET AL: "Efficient Carboazidation of Alkenes Using a Radical Desulfonylative Azide Transfer Process", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》, vol. 132, no. 49, 17 November 2010 (2010-11-17), pages 17511 - 17515 * |
| PHILIPPE RENAUD ET AL: "Total Synthesis of(±)-Cylindricine C", 《ORGANIC LETTERS》, vol. 13, no. 18, 12 August 2011 (2011-08-12), pages 4774 - 4777 * |
| 李明等: "选择性糖苷化合成二糖甾体皂苷", 《中国海洋大学学报》, vol. 42, no. 11, 30 November 2012 (2012-11-30) * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112094310A (en) * | 2020-09-01 | 2020-12-18 | 南京师范大学 | Glucosinolate sterol glycoside and glucosinolate stanol glycoside, and preparation method and application thereof |
| CN112094310B (en) * | 2020-09-01 | 2022-05-03 | 南京师范大学 | Glucosinolate sterol glycoside and glucosinolate stanol glycoside, and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103265608B (en) | 2015-04-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Pettit et al. | Antineoplastic agents. 104. Isolation and structure of the Phyllanthus acuminatus vahl (Euphorbiaceae) glycosides | |
| CN110903340B (en) | Tetracyclic triterpene derivative, and pharmaceutical composition and application thereof | |
| CN103193858A (en) | Synthetic method of spirosolane glycoalkaloids | |
| CN110776544B (en) | 2,3-unsaturated galactosucrose compounds and synthetic method thereof | |
| Chen et al. | Convergent synthesis and cytotoxic activities of 26-thio-and selenodioscin | |
| CN107266410A (en) | A kind of 8 epi puupehedione synthetic method | |
| Nugroho et al. | Dysotriflorins A–M, triterpenoids from Dysoxylum densiflorum | |
| Korda et al. | New lupane bidesmosides exhibiting strong cytotoxic activities in vitro | |
| CN103265608B (en) | Solanidine type glycoalkaloid and convergent synthesis method thereof | |
| CN101735300B (en) | Method for preparing 6beta,7beta-methylene-steride-3beta,5beta-diol | |
| AU2005338556A1 (en) | Novel loganin analogues and a process for the preparation thereof | |
| Saloranta et al. | Increasing the amphiphilicity of an estradiol based steroid structure by Barbier-allylation–ring-closing metathesis–dihydroxylation sequence | |
| CN1295246C (en) | Chemosynthesis of glucuronide oleanane type double sugar chains triterpenoid saponin | |
| Marder et al. | Baccatin III derivatives: Reduction of the C-11, C-12 double bond | |
| CN106083804A (en) | A kind of synthetic method of octatomic ring lactone compound | |
| Xu et al. | Total synthesis, structure revision and cytotoxic activity of Sch 53825 and its derivatives | |
| Yang et al. | Synthesis and crystal structures of two C24 epimeric 3-acetyled 20 (R)-ocotillol type sapogenins obtained from 20 (R)-protopanaxadiol | |
| CN113135931B (en) | Synthesis method of cytochalasin compound flaviperine A | |
| CN104098627B (en) | Seleno derivative of N-trifluoroacetyl epidaunorubicin as well as preparation method and application thereof | |
| CN114644679B (en) | Glucuronide compound, preparation method and application thereof | |
| Khusnutdinova et al. | Stereospecific oxidation of diacetoxyheterobetulin with ozone and dimethyldioxirane | |
| CN102731610A (en) | 26-thio or -seleno spirostanol saponin, synthesis method and application thereof | |
| Bhattacharya et al. | Boron trifluoride-acetic anhydride catalysed rearrangement of dihydroarteannuin B | |
| CN102002093B (en) | Method for preparing triptolide derivative | |
| CN110218230A (en) | Vitamin C is coupled platinum complex, wherein mesosome, preparation method, pharmaceutical composition and purposes |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |