CN102731610B - 26 sulfo-s or seleno spirostanol saponin, its synthetic method and application - Google Patents

26 sulfo-s or seleno spirostanol saponin, its synthetic method and application Download PDF

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CN102731610B
CN102731610B CN201210241555.6A CN201210241555A CN102731610B CN 102731610 B CN102731610 B CN 102731610B CN 201210241555 A CN201210241555 A CN 201210241555A CN 102731610 B CN102731610 B CN 102731610B
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seleno
thio
acid
spirostanol
sapogenin
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CN102731610A (en
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李明
陈朋伟
王鹏
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Ocean University of China
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Abstract

The present invention relates to a kind of 26 sulfo-s or seleno spirostanol saponin and chemical synthesis process thereof, the method comprises the steps: (1) 26 sulphonates of pseudo-spirostanol saponin unit and the nucleophilic reagent of sulphur or selenium react, and obtain 26 S or Se substitution products; (2) again with alkali, or reductive agent and acid-respons obtain 26 sulfo-s or seleno spirostanol saponin unit; (3) continue with acyl group, silica-based protection rhamnosyl three chlorimide ester to precursor reactant, obtain chacotriose sulphur glycosides, then through hydrolysis, with Trichloroacetonitrile react be converted into chacotriose three chlorimide esters to body; (4) react with the glycosyl donor of acyl group, alkyl and silica-based protection again, at the chacotriose that its 3 OH introduce full guard, obtain 26 sulfo-s of the full guard of α, β two kinds of configurations or the spirostanol saponin of seleno; (5) slough all protecting groups and obtain 26 sulfo-s or seleno spirostanol saponin.This compounds has stronger anti-tumor activity, can be used for the preparation of antitumor drug.

Description

26Thio-or seleno-spirostanol saponin, and synthesis method and application thereof
Technical Field
The invention belongs to the field of drug synthesis, and relates to thio-or seleno-spirosteroid saponin, a chemical synthesis method thereof and application thereof in the aspect of tumor resistance.
Technical Field
Spirostanol saponins are widely distributed in plants and have various biological activities: anti-tumor, anti-viral, anti-bacterial, anti-inflammatory and immuno-stimulating activities. Dioscin is one of the most representative spirostanin and is now the saponin most widely used in medical treatment [ Viviane, S.P.; Alemandre, T.C.; Taketa, G.G ].J. Braz. Chem. Soc.2002,13,135–139]. A large number of experiments show that the activity of the spirostanin is determined by sugar chains and aglycones, and the number and the size of the sugar chains, the type of glycosyl, the spatial configuration and the position of the glycosidic bond, the isomerization and the substitution of hydroxyl on the glycosyl and the like all have important influence on the activity of the spirostanin.
The classical bioisosteres of sulfur and selenium as oxygen are often used for structural optimization of lead compounds, and organic sulfur and selenium compounds have recently received more and more attention due to their good biological activities [ (a) yangxinan, youngUniversity of Guizhou university newspaper，2004,22, 104–112; (b) Hu, C.; Zhang, P.; Li, Y.; Liu, B.Chemistry,2002,3, 162–166; (c)Govindasamy, M.; Wolf-Walther, M.; Helmut, S.;Chem. Rev. 2001,101,2125–2179]. Although there have been reports of chemical synthesis of sulfur-or selenium-substituted spirostanol sapogenins [ (a) Uhle, f.c.;J. Org. Chem. 1962,27, 2797–2799; (b) Quan, H. J.; Koyanagi. J.; Ohmori, K.; Uesato,S.; Tsuchido, T.; Saito, S.Eur. J. Med. Chem. 2002,37,659–669]however, no report about the synthesis and application of 26-thio-or seleno-spirostanol saponin is found at present.
Disclosure of Invention
The invention aims to provide 26-thio or seleno spirostane saponin which is synthesized by taking pseudo spirostane sapogenin and potato trisaccharide as raw materials.
The invention also aims to provide a chemical synthesis method of the thio-or seleno-spirosteroid saponin and an application of the thio-or seleno-spirosteroid saponin in the aspect of tumor resistance.
The 26-thio or seleno spirosteroid saponin of the invention has the following structure:
R1- R8is any one of hydrogen, acyl or alkyl;
the potato trisaccharide and the derivative thereof are connected with an aglycone alpha or beta glycosidic bond;
the acyl group is C2- C6Straight or branched aliphatic acyl group of (1) or (C)6- C10The aromatic acyl group of (1);
the alkyl is methyl (Me), ethyl (Et), n-propyl (n-Pr) or isopropyl (i-Pr）；
The absolute configuration of the 22-carbon of the spirostanol saponin isRThe absolute configuration of the carbon at position 25 beingROrS。
The method for synthesizing the 26-thio or seleno spirostanin comprises the following steps:
(1) synthesizing 26-thio or seleno pseudo spirostanol sapogenin:
in a solvent or in the presence of a phase transfer catalyst, reacting 26-site sulfonate of the pseudo-spirostanol sapogenin with a nucleophilic reagent of S or Se to obtain a corresponding 26-site S or Se substituted product;
(2) synthesizing 26-thio or seleno spirostanol sapogenin:
reacting 26-S or Se substituted pseudospirostanol sapogenin with alkali or a reducing agent and acid at 0-150 ℃ to obtain 26-thio or seleno spirostanol sapogenin;
(3) preparation of potato trisaccharide donor:
in the presence of a dehydrating agent, Lewis acid or protonic acid is used as an accelerating agent, 3, 6-di-oxygen-benzoyl-beta-D-glucothioglycoside reacts with acyl and silicon-based protected rhamnose trichloroimido ester donor to obtain potato trisaccharide thioglycoside, and then the potato trisaccharide thioglycoside is hydrolyzed and reacts with trichloroacetonitrile to be converted into the trichloroimido ester donor of potato trisaccharide;
(4) introduction of a 3-position sugar group:
in the presence of a dehydrating agent, using Lewis acid or protonic acid as an accelerating agent, reacting 26-thio or seleno spirostanol sapogenin with acyl or alkyl and a glycosyl donor protected by silicon base, and introducing fully-protected potato trisaccharide into 3-OH of the 26-thio or seleno spirostanol sapogenin to obtain fully-protected 26-thio or seleno spirostanol saponin with alpha and beta configurations;
(5) synthesis of 26-thio or seleno spirosteroid saponin:
under the condition of alkali, all protecting groups of the completely protected spirost saponin are respectively removed to obtain 26-thio or seleno spirost saponin or derivatives thereof.
The method comprises the following specific steps:
(1) synthesizing 26-thio or seleno pseudo spirostanol sapogenin:
reacting the sulfonate of the 26-bit pseudo-spirostanol sapogenin with a nucleophilic reagent of sulfur or selenium at 0-150 ℃ for 1-10 hours in a solvent or in the presence of a phase transfer catalyst to obtain a 26-bit S or Se substituted product; wherein the molar ratio of the sulfonic acid ester to the nucleophilic reagent is 1.0 (1.0-5.0);
the solvent is organic solvent, water or the mixture of the organic solvent and the water;
the organic solvent is C1- C6Halogenated hydrocarbon of (2), 1, 4-dioxane, diethyl ether (Et)2O), acetonitrile (CH)3CN), 2,2, 2-trimethylacetonitrile (t-BuCN), Tetrahydrofuran (THF),N,N-Dimethylformamide (DMF),N,N-one or a mixture of Dimethylacetamide (DMA), Hexamethylphosphoramide (HMPA), tolueneAn agent;
the nucleophilic reagent is KSCOCH3、Na2S2、Li2S2、Cs2S2、K2S2Any one of them or KSeCOCH3、Na2Se2、Li2Se2、Cs2Se2、K2Se2Any one of the above;
the phase transfer catalyst is one of tetrabutylammonium bromide (TBAB), tetrabutylammonium iodide (TBAI), tetrabutylammonium hydrogen sulfate (TBAH), 18-crown-6 (18-C-6) and polyethylene glycol-400 (PEG-400).
(2) Preparing 26-thio or seleno spirostanol sapogenin:
hydrolyzing the S or Se substituted pseudospirostanol sapogenin under the action of alkali in a solvent at 0-150 ℃, and refluxing in an acid solution, or reducing with a reducing agent in the presence of acetic acid for 0.1-10 hours to obtain 26-thio-or seleno-spirostanol sapogenin; the molar ratio of the substitution product to alkali or reducing agent is 1.0 (2.0-20.0) to 2.0-5.0;
the base may be an inorganic base, such as one of sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate; or one of organic alkali potassium tert-butoxide, sodium methoxide, sodium ethoxide and methoxy magnesium;
the acid solution is 0.1-1 mol/L hydrochloric acid methanol or ethanol solution.
(3) Preparation of potato trisaccharide donor:
in the presence of an organic solvent and a dehydrating agent, 3, 6-di-oxygen-benzoyl-beta-D-glucosinolate reacts with acyl and silicon-based protected rhamnose trichloroimino ester donor for 1 to 10 hours at the temperature of between 78 ℃ below zero and 40 ℃ by taking Lewis acid or protonic acid as an accelerating agent to obtain potato trisaccharide glucosinolate, and then the potato trisaccharide glucosinolate is hydrolyzed and reacted with trichloroacetonitrile to be converted into trisaccharide trichloroimino ester donor;
the mol ratio of the 3, 6-di-oxygen-benzoyl-beta-D-glucothioglycoside to the rhamnose donor and the accelerator is 1.0 (1.0-5.0) to 0.05-0.5; the weight ratio of the 3, 6-di-oxygen-benzoyl-beta-D-glucosinolate to the dehydrating agent is 1.0 (3.0-10.0);
the dehydrating agent is 3A, 4A, 5A molecular sieve or an acid-washed 3A molecular sieve (AW-3A) or one of anhydrous sodium sulfate, anhydrous calcium sulfate, anhydrous copper sulfate, anhydrous magnesium sulfate, or a mixture thereof;
the Lewis acid is C1- C6One of trialkylsilyl trifluoromethanesulfonate, boron trifluoride diethyl ether, silver trifluoromethanesulfonate, copper trifluoromethanesulfonate, zinc trifluoromethanesulfonate, scandium trifluoromethanesulfonate, lanthanum trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate, indium trifluoromethanesulfonate, trifluoromethanesulfonic acid, perchloric acid, tetrafluoroboric acid, tetrakis (pentafluorophenyl) boronic acid or bis (trifluoromethanesulfonyl) imide;
said acyl group being C1- C8Fatty acyl radical, C6- C10Aromatic acyl radical, C7- C10Aromatic halohydrocarbon (such as benzyl chloride, p-methoxybenzyl chloride), silicon base C1-C6Trialkyl silicon base.
(4) Introduction of 3-position potato trisaccharide:
in the presence of an organic solvent and a dehydrating agent, under the temperature of-78-40 ℃, by taking Lewis acid or protonic acid as an accelerant, 26-position thio-and seleno-spirostanol sapogenin reacts with an acyl or/and silicon-based protected potato trichloroimine ester donor for 1-10 hours, and fully protected potato trisaccharide is introduced into 3-position OH of the 26-position thio-or seleno-spirostanol sapogenin to obtain fully protected 26-position thio-or seleno-spirostanol saponin with alpha and beta configurations;
the molar ratio of the 26-th thio or seleno spirostanol sapogenin to the glycosyl receptor and the accelerant is 1.0 (1.0-5.0) to 0.05-0.5; the weight ratio of the 26-position thio-seleno spirostanol sapogenin to the dehydrating agent is 1.0 (3.0-10.0);
the dehydrating agent is 3A, 4A, 5A molecular sieve or an acid-washed 3A molecular sieve (AW-3A) or one of anhydrous sodium sulfate, anhydrous calcium sulfate, anhydrous copper sulfate, anhydrous magnesium sulfate, or a mixture thereof;
the Lewis acid is C1- C6One of trialkylsilyl trifluoromethanesulfonate, boron trifluoride diethyl ether, silver trifluoromethanesulfonate, copper trifluoromethanesulfonate, zinc trifluoromethanesulfonate, scandium trifluoromethanesulfonate, lanthanum trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate, indium trifluoromethanesulfonate, trifluoromethanesulfonic acid, perchloric acid, tetrafluoroboric acid, tetrakis (pentafluorophenyl) boronic acid or bis (trifluoromethanesulfonyl) imide;
said glycosyl donor is C1- C8Straight or branched aliphatic acyl, C7- C10Aromatic acyl, silicon radical being C1- C6And (3) protection by trialkyl silicon base.
(5) Synthesis of 26-thio or seleno spirosteroid saponin:
in a solvent, under the condition of-20 to 60 ℃, fully-protected 26-thio-or seleno-spirostanin with alpha and/or beta configuration respectively reacts for 10 to 60 hours in the presence of alkali to remove all protecting groups to obtain the 26-thio-or seleno-spirostanin with alpha and/or beta configuration; the alkali is inorganic or organic alkali; the molar ratio of the fully-protected spirostanin to alkali or a hydrogenation catalyst is 1.0 (0.2-20);
the base may be an inorganic base, such as one of sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate; or one of organic alkali potassium tert-butoxide, sodium methoxide, sodium ethoxide and methoxy magnesium.
The method of the invention is recommended to be carried out under the protection of inert gases, such as argon, nitrogen and the like.
The invention relates to application of 26-thio or seleno spirostanol saponin in preparing an anti-tumor medicament.
The invention provides a chemical method for simply, conveniently and effectively synthesizing 26-thio or seleno spirosteroid saponin and derivatives thereof, and the compounds have stronger antitumor activity and can be used for preparing antitumor drugs.
Drawings
FIG. 1 is a process for the synthesis of 26-position thio-or seleno-diosgenin.
FIG. 2 shows 26-th thio-or seleno-dioscin13 β,14 βAnd isomers thereof13 A and 14 αthe synthesis process of (1).
Detailed Description
The following description will be made in detail with reference to the accompanying drawings and taking the preparation of 26-th thio-and seleno-diosgenin and its alpha isomer and antitumor application as specific examples, but the invention is not limited to the following.
（ 1 ） 26 Synthesis of thio-or seleno-diosgenin
As shown in figure 1, the reagents and conditions in the synthesis reaction of 26-position thio-or seleno-diosgenin are (a) KSCOCH3,DMF, 60℃, 96%; (b) (i) KOH, MeOH, H2O；(ii) HCl, EtOH, H2O, reflux, 87%; (c) CsOH·H2O, Se, N2H4·H2O, DMF, 60℃,92%; (d) (i) Zn, CH3COOH, 150oC；(ii) KOH, EtOH, H2O, dioxane, 87%。
The specific experimental procedures and data are as follows:
compound (I)2The synthesis of (2):
under the protection of argon, sulfonate1(369 mg, 0.65mmol) [(a) Uhle, F. C.J. Org. Chem. 1962,97, 2797–2799; (b) Zha, X.; Sun, H.; Hao, J.; Zhang, Y.Chem. Biodiv. 2007,4, 25–31]Dissolved in 5mL DMF and then KSCOCH was added3(222mg, 1.95 mmol, 3.0 equiv.). After stirring the reaction at room temperature for 10 h, TLC showed complete reaction, concentration under reduced pressure, CH2Cl2After dilution, the mixture is washed by saturated NaCl and Na2SO4Drying, filtering, concentrating, and performing flash column chromatography to obtain 26-thioacetyl substituted compound2(295mg, 0.62 mmol, 96%)。
[α] = -22.8 (c1.00, CHCl3)；
1H NMR (600 MHz, CDCl3): 5.32 (d, 1H,J= 5.4 Hz), 4.73-4.69 (m, 1H),3.51-3.47 (m, 1H), 2.91 (dd, 1H,J= 13.2, 5.4 Hz), 2.75 (dd, 1H,J= 13.2, 7.2 Hz), 2.44 (d, 1H,J= 10.2 Hz), 2.30 (s, 3H), 1.56 (s, 3H),1.00 (s, 3H), 0.93 (d, 3H,J= 6.6 Hz), 0.66 (s, 3H)。
13C NMR(150 MHz, CDCl3): 195.9, 151.3, 140.8, 121.3, 103.7, 84.2, 71.5, 64.1, 54.9, 50.0, 43.2, 42.2,39.4, 37.2, 36.5, 35.6, 34.0, 33.2, 32.8, 32.1, 31.5, 31.2, 30.6, 23.2, 20.9,19.3, 18.9, 13.9, 11.6。
HRMS(ESI):[M + H]+, C29H45O3S, calculating a value: 473.3084, respectively; measured value: c29H45O3S473.3090。
Compound (I)3The synthesis of (2):
under the protection of argon, the compound is added2(295 mg, 0.62mmol) was dissolved in 20mL of methanol, and 5mL of methanol/water (MeOH: H) containing KOH (70 mg, 1.23 mmol, 2.0equiv.) were added2O = 9: 1) solution. After the mixture was stirred at room temperature for 15 min, TLC showed completion of the reaction, followed by addition of 6 mol/L aqueous hydrochloric acid (320. mu.L, 1.87 mmol, 3.0 equiv.), stirring at room temperature for 30min, storage at 0 ℃ for 12 h, collection by filtrationAnd (3) a solid. The solid was dried and dissolved in 20mL of ethanol/water under argon (EtOH: H)2O = 19: 1), then adding 0.5 mL of 37% concentrated HCl, heating and refluxing for 5 h, cooling, pouring into ice water, filtering, collecting solid, and further purifying by flash column chromatography to obtain the spirostanol sapogenin with the S position at 26 substituted3(209mg, 0.48 mmol, 87%)。
[α] = -162.7 (c1.10, CHCl3)；
1H NMR (600 MHz, CDCl3): 5.34 (d, 1H,J= 4,8 Hz), 4.62 (dd, 1H,J= 15.0, 7.2 Hz), 3.55-3.48 (m, 1H), 2.52 (t, 1H,J= 13.2 Hz), 2.28 (d,2H,J= 13.2 Hz), 2.22 (t, 1H,J= 12.6 Hz), 1.01 (s, 3H), 1.00(d, 3H,J= 8.4 Hz), 0.92 (d, 3H,J= 6.6 Hz), 0.80 (s, 3H)。
13C NMR(150 MHz, CDCl3): 140.8, 121.4, 97.5, 81.6, 71.7, 62.8, 56.6, 50.0, 44.4, 42.2, 40.3, 39.7, 38.5,37.2, 36.6, 33.3, 32.1, 32.0, 31.7, 31.6, 31.41, 31.38, 22.4, 20.8, 19.4,16.5,16.2。
HRMS(ESI):[M + H]+, C27H43O2S, calculating a value: 431.2978, respectively; measured value: c27H43O2S431.2983。
Compound (I)4The synthesis of (2):
under the protection of argon, CsOH & H2O (76 mg, 0.45 mmol) and selenium powder (23.7mg, 0.30 mmol) were added to 2 mL DMF and N was added dropwise at room temperature2H4·H2O (55. mu.l, 0.90 mmol), stirred for 2h, and then sulfonate was added1(171mg, 0.30 mmol), then warmed to 60 ℃ and stirred for 4h further, and then concentrated under reduced pressure. The residue is substituted by CH2Cl2After dilution, the column was washed with saturated NaCl. Na for organic phase2SO4Drying, filtering and concentratingCondensing and fast silica gel column chromatography to obtain diselenide4(132mg, 0.14 mmol, 92%)。
[α] =34.2(c1.21, CHCl3)；
1H NMR (600 MHz, CDCl3) 5.34 (d, 2H,J= 4.8 Hz), 4.75-4.70 (m, 2H),3.53-3.49 (m, 2H), 3.02 (dd, 2H,J= 12.0, 5.4 Hz), 2.82 (dd, 2H,J= 12.0, 7.8 Hz), 2.45 (d, 2H,J= 10.2 Hz), 2.30 (m, 4H), 2.22 (t, 4H,J= 10.8 Hz) 1.58 (s, 6H), 1.01 (s, 6H), 0.99 (d, 6H,J= 6.6 Hz), 0.68(s, 6H)。
13C NMR(150 MHz, CDCl3) 151.5, 140.8,121.3, 103.7, 84.3, 71.6, 64.2, 55.0 , 50.0, 43.2, 42.2, 39.5, 39.1, 37.2,36.6, 34.1, 33.9, 33.8, 32.2, 31.6, 31.2, 23.4, 21.0, 19.5, 19.4, 14.0, 11.7。
Compound (I)5The synthesis of (2):
under the protection of argon, diselenide430 mL of acetic acid was added to a mixture of (286mg, 0.30 mol) and zinc powder (59 mg, 0.90 mmol, 3.0 equiv.), and the reaction was heated under reflux for 24 h, after which TLC showed completion. The residue obtained is concentrated under reduced pressure, dissolved in 25 mL of dioxane under argon protection, and then 20mL of a 10% KOH ethanol/water mixed solution (EtOH: H)2O = 1: 1), stirred at room temperature for 24 hours, and then poured into ice water and added with CH2Cl2And (4) extracting. The organic phase is washed by saturated NaCl and Na2SO4Drying, filtering, concentrating, and performing flash column chromatography to obtain compound5(250 mg，0.52 mmol，87%)。
[α] = -192.8 (c1.00, CHCl3)；
1H NMR (600 MHz, CDCl3): 5.34 (d, 1H,J= 4.8 Hz), 4.64 (dd, 1H,J= 15.6, 7.8 Hz), 3.53-3.50 (m, 1H), 2.58 (t, 1H,J= 12.0 Hz), 2.37-2.34(m, 1H), 2.31-2.28 (m, 1H), 2.25-2.20 (m, 2H), 2.04-1.97 (m, 2H), 1.02 (d, 3H,J= 7.2 Hz), 1.01 (s, 3H), 0.96 (d, 3H,J= 6.6 Hz), 0.80 (s, 3H)。
13C NMR(150 MHz, CDCl3): 140.8, 121.4, 97.9, 82.7, 71.7, 62.9, 56.6, 50.0, 45.4, 42.2, 40.4, 40.1, 39.7,37.2, 36.6, 34.0, 32.6, 32.0, 31.6, 31.4, 31.1, 24.8, 23.7, 20.8, 19.4, 17.7,16.6。
（ 2 ) A potato trisaccharide donor, 26 Synthesis of sulfo-or seleno-dioscin and alpha isomer thereof
As shown in FIG. 2, a potato trisaccharide donor1026-thio or seleno dioscin13 β,14 βAnd isomers thereof13 A and 14 αthe reagents and conditions in the synthesis reaction of (a) are: (a) TMSOTf, CH2Cl2,-30oC; (b) NBS, acetone-H2O, 72% (2-step reaction); (c) Cl3CCN,DBU, CH2Cl2, 91%; (d)3Or5, 4 Å MS, TMSOTf, CH2Cl2,46% for11 α； 27%for11 β;,32% for12 α; 46% for12 β; (e)CH3ONa, CH3OH : CH2Cl2= 1 : 1, 99%for13 α; 95% for13 β; 90% for14 α; 78%for14 β.
Article of manufacture10The synthesis of (2):
under the protection of argon, the compound is added6[Song, G.; Yang,S.; Zhang, W.; Cao, Y.; Wang, P.; Ding, N.; Zhang, Z.; Guo, Y.; Li, Y.J. Med. Chem.2009,52, 7368–7371.](1.73 g, 3.50 mmol), freshly activated 4A molecular sieve (2.30 g) was added anhydrous CH2Cl2(30 mL) at-30 ℃ for 30min,TMSOTf (126. mu.L, 0.70 mmol) was added, stirred for 10 min and then the compound was added7[(a) Kitagawa, I.; Back, N. I.; Ohashi,K.; Sakagami, M.; Yoshikawa, M.; Shibuya,Chem. Pharm. Bull.1989,37,1131–1133; (b) Cheng, M. S.; Wang, Q. L.;Tian, Q.; Song, H. Y.; Liu, Y. X.; Li, Q.; Xu, X.; Miao, H. D.; Yao, X. S.;Yang, Z.J. Org. Chem.2003,68, 3658–3662.](4.56 g, 10.49 mmol) of CH2Cl2Solution (5 ml), stirring at-30 deg.C for 2 hr, detecting by TLC until reaction is complete, adding Et3Quenching reaction by N, decompression concentrating, and quick column chromatography to obtain the compound8And compounds7Mixtures of anomeric hydrolysates.
Dissolving the product obtained in the above step in 30 mL acetone/water (9: 1) under the protection of argon, adding NBS (1.16 g, 6.50 mmol) under ice bath, stirring for 30min, then TLC shows complete reaction, and adding saturated NaHCO dropwise3Quenching reaction, vacuum concentrating to remove acetone, and using CH to make residual liquor2Cl2After dilution, the organic phase is collected by separation and then successively diluted with saturated NaHCO3Washing with saturated NaCl, and passing through anhydrous NaSO4Drying, filtering, concentrating, and performing flash column chromatography to obtain compound9(2.34 g, 2.51mmol, 72% yield over two steps).
Under the protection of argon, the compound is added9(1.92 g, 2.06 mmol) in CH2Cl2(25 mL), DBU (125. mu.L, 0.82 mmol) was added under ice-cooling, stirred for 5 min and Cl was slowly added dropwise3After CCN (2.06 mL, 20.58 mmol) is heated to room temperature and reacts for 2h, TLC shows that the reaction is complete, and the reaction solution is decompressed, concentrated and subjected to flash column chromatography to obtain a compound10(2.02 g, 1.87 mmol, 91%)。
[α] =103.2 (c1.05, CHCl3)；
1H NMR (600 MHz, CDCl3): 8.74 (s, 1H), 8.05 (m, 4H), 7.59-7.54 (m, 2H), 7.47-7.43(m, 4H), 6.48 (d, 1H,J= 3.6 Hz), 5.89 (t, 1H,J= 10.2 Hz),5.20 (dd, 1H,J= 9.6, 3.0 Hz), 5.15 (dd, 1H,J= 3.6, 1.8 Hz),5.11 (dd, 1H,J= 9.6, 3.6 Hz), 4.93-4.87 (m, 3H), 4.83-4.80 (m, 2H),4.79 (d, 1H,J= 1.2 Hz), 4.51 (dd, 1H,J= 12.6, 3.6 Hz),4.33-4.30 (m, 1H), 4.10 (t, 1H,J= 9.6 Hz), 4.05 (dd, 1H,J=10.2, 4.2 Hz), 3.90-3.87 (m, 1H), 3.78-3.75 (m, 1H), 2.00 (s, 3H), 1.98 (s,3H), 1.95 (s, 3H), 1.93 (s, 3H), 1.86 (s, 3H), 1.85 (s, 3H), 1.13 (d, 3H,J=6.6 Hz), 0.69 (d, 3H,J= 6.0 Hz)。
13C NMR(150 MHz, CDCl3): 169.92, 169.88, 169.86, 169.82, 169.2, 169.0, 165.7, 165.1, 161.2, 133.2,133.1, 129.9, 129.7, 129.6, 129.2, 128.3, 99.4, 99.1, 94.1, 90.6, 76.3, 72.3,71.5, 70.8, 70.5, 69.9, 69.3, 68.4, 68.1, 67.5, 67.2, 62.0, 60.3, 20.65, 20.61,20.45, 20.38, 17.2, 16.8, 14.1。
HRMS(ESI):C46H52NO22Cl2 37Cl, calculated: 1077.2012, respectively; measured value: 1077.1991.
compound (I)11 α，11 βThe synthesis of (2):
under the protection of argon, the compound is added3(86 mg, 0.20mmol) was dissolved in 4 mL of anhydrous CH2Cl2To this was added dried 4 a molecular sieve (300 mg), stirred at-30 ℃ for 30min, then trifluoromethylsilyl triflate (TMSOTf) (7 μ L, 0.04 mmol, 0.2equiv.) was added, and after stirring for a further 10 min, ester group protected trisaccharide donor was added10(280 mg, 0.26mmol, 1.30 equiv.), -30 ℃ stirring for 4h, TLC shows complete reaction, triethylamine quenches reaction, and white solid is obtained by filtering, concentrating and flash column chromatography11 α(125mg, 0.093mmol, 46%) and11 β(73mg, 0.054mmol, 27%)。
compound (I)11 α：
[α] =76.6 (c0.80, CHCl3)；
1H NMR (600 MHz, CDCl3): 8.05-8.03 (m, 4H), 7.56-7.51 (m, 2H), 7.43-7.39 (m, 4H),5.77 (t, 1H,J= 9.6 Hz), 5.25 (d, 1H,J= 4.2 Hz ), 5.22 (dd,1H,J= 10.2, 3.6 Hz), 5.17 (dd, 1H,J= 10.2, 3.6 Hz), 5.15-5.11(m, 1H), 5.05 (d, 1H,J= 3.6 Hz), 4.90 (t, 1H,J= 9.6 Hz), 4.89(t, 1H,J= 10.2 Hz), 4.85 (d, 1H,J= 1.8 Hz), 4.77-4.72 (m,3H), 4.63 (dd, 1H,J= 15.6, 7.2 Hz), 4.52 (dd, 1H,J= 12.6, 5.4Hz), 4.29-4.26 (m, 1H), 3.91-3.86 (m, 2H), 3.80-3.75 (m, 1H), 3.72 (dd, 1H,J= 9.6, 3.0 Hz), 3.48-3.42 (m, 1H), 2.53 (t, 1H,J= 13.2 Hz), 2.47 (d,2H,J= 7.8 Hz), 2.28 (d, 1H,J= 12.6 Hz), 2.01 (s, 3H), 1.98(s, 3H), 1.95 (s, 3H), 1.93 (s, 3H), 1.87 (s, 3H), 1.85 (s, 3H), 1.12 (d, 3H,J= 6.0 Hz), 1.05 (s, 3H), 1.00 (d, 3H,J= 7.2 Hz), 0.92 (d, 3H,J= 6.6 Hz), 0.80 (s, 3H), 0.69 (d, 3H,J= 6.0 Hz)。
13C NMR(150 MHz, CDCl3): 170.0, 169.90, 169.87, 169.2, 165.9, 165.2, 140.1, 132.99, 132.96, 129.83,129.77, 129.71, 129.6, 128.3, 128.2, 121.9, 99.4, 99.0, 97.5, 96.2, 81.6, 79.1,78.7, 77.8, 72.4, 71.1, 70.6, 70.1, 69.5, 68.8, 68.5, 68.3, 67.4, 66.8, 62.8,56.6, 49.9, 44.3, 40.3, 40.0, 39.7, 38.4, 37.0, 36.7, 33.2, 32.0, 31.7, 31.4,31.3, 27.8, 22.4, 20.73, 20.67, 20.5, 19.3, 17.4, 16.8, 16.5, 16.2。
HRMS(ESI):[M + Na]+, C71H92O23SNa, calculated: 1367.5642, respectively; measured value: 1367.5691.
compound (I)11 β：
[α] =34.6 (c0.80, CHCl3)；
1H NMR (600 MHz, CDCl3): 8.04-8.01 (m, 4H), 7.55-7.52 (m, 2H), 7.44-7.38 (m, 4H),5.60 (t, 1H,J= 9.4 Hz), 5.33 (d, 1H,J= 5.4 Hz), 5.14-5.11 (m,2H), 5.09 (m, 1H), 4.95-4.93 (m, 1H), 4.89 (t, 1H,J= 10.4 Hz), 4.85(t, 1H,J= 10.2 Hz), 4.83 (brs, 1H), 4.77 (d, 1H, J = 11.52 Hz), 4.74(brs, 1H), 4.65 (d, 1H,J= 7.68 Hz), 4.64-4.60(m, 1H), 4.49 (dd, 1H,J= 12.0, 5.4 Hz), 4.35-4.30 (m, 1H), 3.94 (t, 1H,J= 9.6 Hz),3.85-3.81 (m, 1H), 3.77 (t, 1H,J= 7.2 Hz), 3.70-3.66 (m, 1H),3.58-3.53 (m, 1H), 2.52 (t, 1H,J= 11.4 Hz), 2.38 (d, 1H,J=10.8 Hz), 2.28 (d, 1H,J= 11.4 Hz), 2.23 (t, 1H,J= 12.6 Hz),1.96 (s, 6H), 1.92 (s, 3H), 1.90 (s, 3H), 1.86 (s, 3H), 1.72 (s, 3H), 1.13 (d,3H,J= 6.0 Hz), 1.00 (d, 3H,J= 6.6 Hz), 0.93 (s, 3H), 0.90 (d,3H,J= 6.0 Hz), 0.78 (s, 3H), 0.66 (d, 3H,J= 6.0 Hz)。
13C NMR(150 MHz, CDCl3): 169.93, 169.88, 169.80, 169.6, 168.8, 165.7, 164.9, 140.0, 133.2, 132.9, 132.3,130.8, 130.0, 129.8, 129.7, 129.0, 128.8, 128.34, 128.31, 121.9, 99.4, 98.9,98.0, 97.4, 81.5, 79.4, 77.3, 76.1, 75.9, 72.9, 71.7, 71.0, 70.4, 70.0, 69.1,68.7, 68.4, 67.5, 66.4, 62.7, 56.5, 49.8, 44.3, 40.2, 39.6, 38.45, 38.36, 36.8,36.7, 33.2, 32.02, 31.99, 31.7, 31.3, 29.6, 27.6, 22.4, 20.73, 20.68, 20.65,20.62, 20.5, 20.2, 19.1, 17.1, 16.8, 16.5, 16.1。
HRMS(ESI):[M + Na]+, C71H92O23SNa, calculated: 1367.5642, respectively; measured value: 1367.5696.
compound (I)12 α，12 βThe synthesis of (2):
under the protection of argon, the compound is added5(81 mg, 0.17mmol) was dissolved in 4 mL of anhydrous CH2Cl2To this was added dried 4 a molecular sieve (300 mg), stirred at-78 ℃ for 30min, then trifluoromethylsilyl triflate (TMSOTf) (6 μ L, 0.034 mmol, 0.2equiv.) was added, and after stirring for a further 10 min, ester group protected trisaccharide donor was added10(238 mg, 0.22mmol, 1.30 equiv.), -78 ℃ stirring for 1h, and further-40 ℃ stirring for 3h, after which TLC showed complete reaction. Quenching the reaction by triethylamine, filtering, concentrating, and performing flash column chromatography to obtain white solid12 α(76 mg, 0.055 mmol, 32%) and12 β(110 mg, 0.079 mmol, 46%)。
compound (I)12 α:
[α] = -1.9 (c1.40, CHCl3)；
1H NMR (600 MHz, CDCl3): 8.06 (d, 2H,J= 4.2 Hz), 8.04 (d, 2H,J=4.2 Hz), 7.57-7.52 (m, 2H), 7.44-7.40 (dd, 4H,J= 13.8, 7.8 Hz), 5.78(t, 1H,J= 9.6 Hz), 5.26 (d, 1H,J= 4.2 Hz), 5.23 (dd, 1H,J= 10.2, 3.0 Hz), 5.18 (dd, 1H,J= 9.6, 3.6 Hz), 5.15-5.12 (m, 1H), 5.06(d, 1H,J= 3.6 Hz), 4.93-4.88 (m, 2H), 4.86 (brs, 1H), 4.78-4.76 (m,1H), 4.74 (d, 1H,J= 13.2 Hz), 4.66 (dd, 1H,J= 15.6, 7.2 Hz),4.53 (dd, 1H,J= 12.0, 4.8 Hz), 4.32-4.26 (m, 1H), 3.91-3.89 (m, 2H),3.80-3.77 (m, 1H), 3.73 (dd, 1H,J= 9.6, 3.6 Hz), 3.48-3.43 (m, 1H),2.59 (t, 1H,J= 12.0 Hz), 2.48 (d, 2H,J= 7.8 Hz), 2.37 (d, 1H,J= 11.4 Hz), 2.26-2.20 (m, 1H), 2.02 (s, 3H), 1.99 (s, 3H), 1.96 (s,3H), 1.94 (s, 3H), 1.88 (s, 3H), 1.86 (s, 3H), 1.13 (d, 3H,J= 6.0 Hz),1.06 (s, 3H), 1.02 (d, 3H,J= 7.2 Hz), 0.96 (d, 3H,J= 6.6 Hz),0.81 (s, 3H), 0.69 (d, 3H,J= 6.0 Hz)。
13C NMR(150 MHz, CDCl3): 170.05, 169.93, 169.90, 169.2, 166.0, 165.2, 140.1, 133.02, 132.99, 129.88,129.80, 129.76, 129.6, 128.34, 128.28, 121.9, 99.4, 99.0, 97.9, 96.2, 82.7,79.2, 78.7, 77.8, 72.5, 71.1, 70.7, 70.2, 69.5, 68.9, 68.6, 68.4, 67.4, 66.9,62.9, 56.6, 49.9, 45.4, 40.4, 40.1, 39.7, 37.0, 36.7, 34.0, 32.6, 32.0, 31.3,31.1, 27.9, 24.8, 23.7, 20.8, 20.5, 19.3, 17.7, 17.4, 16.8, 16.6。
HRMS(ESI):[M + Na]+, C71H92O23SeNa, calculated: 1415.5087, respectively; measured value: 1415.5119.
compound (I)12 β：
[α] = -44.5 (c1.70, CHCl3)；
1H NMR (600 MHz, CDCl3): 8.03 (d, 2H,J= 8.4 Hz), 8.01 (d, 2H,J=8.4 Hz), 7.57-7.52 (m, 2H), 7.45-7.39 (m, 4H), 5.60 (t, 1H,J= 9.0 Hz),5.33 (d, 1H,J= 5.4 Hz), 5.15-5.12 (m, 2H), 5.10-5.09 (m, 1H), 4.95(dd, 1H,J= 3.6, 1.8 Hz), 4.89 (t, 1H,J= 9.6 Hz), 4.85 (t, 1H,J= 9.6 Hz), 4.83 (d, 1H,J= 1.8 Hz), 4.77 (dd, 1H,J=12.0, 1.8 Hz), 4.74 (d, 1H ,J= 1.2 Hz), 4.65 (d, 1H,J= 7.8Hz) 4.64 (dd, 1H,J= 12.4, 7.8 Hz), 4.49 (dd, 1H,J= 12.6, 5.4Hz), 4.34-4.31 (m, 1H), 3.95 (t, 1H,J= 9.6 Hz), 3.88-3.82 (m, 1H),3.77 (t, 1H,J= 8.4 Hz), 3.71-3.67 (m, 1H), 3.57-3.53 (m, 1H), 2.57 (t,1H,J= 12.0 Hz), 2.39-2.34 (m, 2H), 2.24-2.18 (m, 2H), 1.96 (s, 6H),1.93 (s, 3H), 1.90 (m, 3H), 1.86 (s, 3H), 1.72 (s, 3H), 1.13 (d, 3H,J=6.6 Hz), 1.01 (d, 3H,J= 6.6 Hz), 0.95 (d, 3H,J= 7.8 Hz) 0.94(s, 3H), 0.78 (s, 3H), 0.66 (d, 3H,J= 6.6 Hz)。
13C NMR(150 MHz, CDCl3): 169.93,169.87, 169.80, 169.5, 168.8, 165.7, 164.9, 140.0, 133.2, 132.9, 130.0, 129.8,129.7, 129.1, 128.34, 128.29, 121.9, 99.4, 98.9, 98.0, 97.8, 82.6, 79.4, 77.3,76.1, 75.9, 72.9, 71.0,70.4, 70.0, 69.1, 68.7, 68.4, 67.5, 66.4, 62.8, 62.7,56.4, 49.8, 45.4, 40.3, 40.1, 39.6, 38.4, 36.8, 36.7, 33.9, 32.6, 32.0, 31.3,31.1, 29.6, 24.8, 23.6, 20.73, 20.67, 20.62, 20.5, 20.2, 19.1, 17.6, 17.1,16.8, 16.5。
HRMS(ESI):[M + Na]+, C71H92O23SeNa, calculated: 1415.5087, respectively; measured value: 1415.5144.
compound (I)13 αThe synthesis of (2):
under the protection of argon, the compound is added11 α(40mg, 0.0297 mmol) in a solvent consisting of 2 ml methanol/dichloromethane (MeOH: CH)2Cl2= 1: 1) mixed solvent, then sodium methoxide (24 mg, 0.44 mmol, 14.6 equiv.) in methanol solution (230 μ L) was added and the reaction was stirred at room temperature for 48 h, TLC showed completion of the reaction. Neutralizing the reaction with acidic resin, filtering to remove solid, concentrating the filtrate, and performing flash column chromatography to obtain white solid13 α(26 mg, 0.0294 mmol, 99%)。
[α] = -46.0 (c0.09, CHCl3MeOH with 8% water = 1: 1);
1H NMR (600 MHz, pyridine- 5d): 5.89 (s, 1H), 5.81 (s, 1H), 5.46 (d,1H,J= 3.0 Hz), 5.27 (d, 1H,J= 3.6 Hz), 4.89-4.83 (m, 1H),4.81-4.76 (m, 2H), 4.69-4.65 (m, 1H), 4.62-4.55 (m, 2H), 4.52-4.48 (m, 1H),4.42-4.37 (m, 2H), 4.33-4.28 (m, 2H), 4.26 (d, 1H,J= 10.2 Hz), 4.21(d, 1H,J= 12.0 Hz), 4.14-4.11 (m, 2H), 3.73-3.68 (m, 1H), 2.64-2.55(m, 2H), 2.49-2.42 (m, 1H), 2.29 (d, 1H,J= 10.8 Hz), 1.66 (d, 3H,J= 6.0 Hz), 1.64 (d, 3H,J= 6.0 Hz), 1.07 (d, 3H,J= 6.0 Hz),0.82 (m, 6H), 0.78 (s, 3H)。
13C NMR(150MHz, pyridine- 5d) 140.8, 121.3, 103.9, 102.7, 97.9, 97.5, 81.7, 79.3, 78.9, 78.4, 73.6, 72.6,72.45, 72.40, 72.3, 72.0, 70.2, 70.0, 63.1, 61.2, 56.4, 49.9, 44.4, 40.5, 40.2,39.5, 38.7, 37.0, 36.6, 33.3, 32.1, 32.0, 31.9, 31.4, 31.3, 28.4, 22.4, 20.8,19.0, 18.4, 18.3, 16.3。
HRMS(ESI):[M + Na]+, C45H72O15SNa, calculated: 907.4484, respectively; measured value: 907.4505.
compound (I)13 βThe synthesis of (2):
according to the synthesis of compounds13 αSame method, from compounds11 β(40mg, 0.0297 mmol) was deprotected to give a white solid13 β(25 mg, 0.0282 mmol, 95%)。
[α] = -97.4 (c0.85, CHCl3MeOH with 8% water = 1: 1);
1H NMR (600 MHz, pyridine- 5d): 6.36 (s, 1H), 5.82 (s, 1H), 5.27 (s,1H), 4.93-4.86 (m, 3H), 4.79-4.75 (m, 2H), 4.64 (brs, 1H), 4.59-4.56 (m, 1H),4.51-4.48 (m, 1H), 4.35-4.28 (m, 3H), 4.19-4.17 (m, 3H), 4.05 (d, 1H,J= 12.6 Hz), 3.86-3.80 (m, 1H), 3.60 (d, 1H,J= 7.8 Hz), 2.74 (d, 1H,J= 12.0 Hz), 2.68 (t, 1H,J= 12.0 Hz), 2.60 (t, 1H,J= 12.6 Hz),2.30 (d, 1H,J= 12.0 Hz), 1.72 (d, 3H,J= 6.0 Hz), 1.58 (d, 3H,J= 6.0 Hz), 1.07 (d, 3H,J= 7.2 Hz), 1.01 (s, 3H), 0.79 (m, 6H)。
13C NMR(150MHz, pyridine- 5d): 140.5, 121.5, 102.6, 101.8, 100.0, 97.5,81.7, 78.2, 77.8, 77.7, 77.5, 76.7,73.8, 73.6, 72.6, 72.4, 72.2, 70.1, 69.2, 63.1, 61.0, 56.4, 50.0, 44.4, 40.2,40.2, 39.5, 38.7, 37.2, 36.8, 33.3, 32.1, 32.0, 31.9, 31.45, 31.39, 29.9, 22.4,20.8, 19.1, 18.4, 18.2, 16.3。
HRMS(ESI):[M + Na]+, C45H72O15SNa, calculated: 907.4484, respectively; measured value: 907.4501.
compound (I)14 αThe synthesis of (2):
according to the synthesis of compounds13 αSame method, from compounds12 αDeprotection (40mg, 0.0287 mmol) gave a white solid14 α(24 mg, 0.0258 mmol, 90%)。
[α] = -87.4 (c0.85, CHCl3MeOH with 8% water = 1: 1);
1H NMR (600 MHz, pyridine- 5d) 5.92 (s, 1H), 5.83 (s, 1H), 5.48 (d,1H,J= 3.0 Hz), 5.27 (d, 1H,J= 3.6 Hz), 4.91-4.85 (m, 1H),4.81-4.76 (m, 2H), 4.68-4.65 (m, 1H), 4.62-4.57 (m, 2H), 4.52 (dd, 1H,J= 9.0, 3.0 Hz), 4.42-4.37 (m, 2H), 4.33-4.28 (m, 2H), 4.26 (d, 1H,J=10.2 Hz), 4.21 (d, 1H,J= 12.0 Hz), 4.14-4.11 (m, 2H), 3.73-3.68 (m,1H), 2.66-2.60 (m, 2H), 2.48 (t, 1H,J= 11.4 Hz), 2.35 (d, 1H,J= 12.0 Hz), 2.26-2.22 (m, 1H), 2.14 (d, 1H,J= 12.0 Hz), 2.00-1.97 (m,1H), 1.93-1.89 (m, 2H), 1.66 (d, 3H,J= 6.0 Hz), 1.64 (d, 3H,J= 6.0 Hz), 1.07 (d, 3H,J= 6.0 Hz), 0.82 (m, 6H), 0.78 (s, 3H)。
13C NMR(150MHz, Pyridine- 5d): 140.8, 121.3, 103.9, 102.7, 98.0,97.9, 82.8, 79.3, 79.0, 78.4, 73.6, 72.6,72.5, 72.4, 72.3, 72.0, 70.2, 70.1, 63.2, 61.2, 56.4, 49.9, 45.4, 40.5, 40.3,39.5, 37.0, 36.7, 34.0, 32.8, 32.0, 31.3, 31.1, 28.4, 24.7, 23.6, 20.8, 19.0,18.4, 18.3, 17.7, 16.4。
HRMS(ESI):[M + Na]+, C45H72O15SeNa, calculated: 955.3929, respectively; measured value: 955.3950.
compound (I)14 βThe synthesis of (2):
according to the synthesis of compounds13 αSame method, from compounds12 βDeprotection (40mg, 0.0287 mmol) gave a white solid14 β(21 mg, 0.0225 mmol, 78%)。
[α] = -148.7 (c0.80, CHCl3MeOH with 8% water = 1: 1);
1H NMR (600 MHz, pyridine- 5d) 6.40 (s, 1H), 5.86 (s, 1H), 5.28 (d,1H,J= 5.4 Hz), 4.97-4.92 (m, 3H), 4.83-4.78 (m, 2H), 4.67 (brs, 1H),4.62 (dd, 1H,J= 9.0, 3.6 Hz), 4.53 (dd, 1H,J= 9.6, 3.6 Hz),4.41-4.30 (m, 3H), 4.22-4.18 (m, 3H), 4.07 (dd, 1H,J= 12.6, 3.6 Hz),3.88-3.83 (m, 1H), 3.62 (d, 1H,J= 9.6 Hz), 2.80-2.75 (m, 1H),2.72-2.69 (d, 1H,J= 11.4 Hz), 2.66 (t, 1H,J= 10.8 Hz), 2.37(d, 1H,J= 11.4 Hz), 2.27-2.23 (m, 1H), 2.04-2.00 (m, 2H), 1.75 (d, 3H,J= 6.0 Hz), 1.62 (d, 3H,J= 6.6 Hz), 1.07 (d, 3H,J=6.6 Hz), 1.02 (s, 3H), 0.83 (d, 3H,J= 6.6 Hz), 0.79 (s, 3H)。
13C NMR(150MHz, pyridine- 5d) 140.5,121.5, 102.6, 101.8, 100.0, 97.8, 82.8, 78.2, 77.7, 77.6, 77.5, 76.6, 73.8,73.6, 72.5, 72.4, 72.2, 70.1, 69.2, 63.2, 61.0, 56.3, 50.0, 45.4, 40.3, 39.4,38.6, 37.2, 36.8, 34.0, 32.8, 32.0, 31.3, 31.2, 29.9, 24.7, 23.6, 20.8, 19.1,18.4, 18.2, 17.7, 16.4。
HRMS(ESI):[M + H]+, C45H73O15se, calculated value: 933.4109, respectively; measured value: 933.4137。
（ 3 ) Antitumor Activity test of Compounds
Compounds were each tested using the MTT method13 β、13 α、 14 βAnd14 αand dioscin [ (a) Deng, S.; Yu, B.; Hui, Y).Tetrahedron Lett. 1998,39, 6511–6514; (b) Tao,H. C.; Yu, B.Tetrahedron Lett. 2001,42, 2405–2407]The results of the inhibitory activities on tumor cell strains A-549, Hela and K562 are shown in Table 1. 26-thio analogs compared to dioscin13 Of betaHas improved activity, but 26-seleno analogue14 βHas slightly lower activity than dioscin, and13 αand14 αthe activity of the isomers is significantly reduced. This suggests that the beta-type glycosidic bond between the sugar chain at the 3-position and the aglycone plays a critical role in its antitumor activity for the spirostanin compounds.
Watch (A) 1 ： 13 α，13 β，14 α，14 βAnd antitumor Activity of Dioscorea opposita Thunb (IC 50)
Compound A-549 Hela K562
Dioscin 4.02 7.86 5.12
13β 3.72 6.68 4.1
13α >10 >10 >10
14β 5.0 >10 4.96
14α >10 >10 >10

Claims (5)

1. A method for synthesizing 26-thio or seleno spirostanin with a structural general formula shown as the following,
wherein,
double bonds (Δ) in positions 5, 65) (ii) a X = S or Se; y ═ H and H;
R1-R8is hydrogen;
the potato trisaccharide and the derivatives thereof are connected with the aglycone by a beta glycosidic bond;
the absolute configuration of the carbon at each of the 22-and 25-positions isR；
The method is characterized by comprising the following steps:
(1) synthesizing 26-thio or seleno pseudo spirostanol sapogenin:
in a solvent or in the presence of a phase transfer catalyst, reacting 26-para-toluenesulfonate of the pseudo-spirostanol sapogenin with a sulfur or selenium nucleophile for 1 to 10 hours at the temperature of between 0 and 150 ℃ to obtain a corresponding sulfur or selenium substituted product; wherein the molar ratio of the p-toluenesulfonate to the nucleophile is 1 (1.0-5.0); the nucleophilic reagent is KSCOCH3、Na2S2、Li2S2、Cs2S2、K2S2One of them or KSeCOCH3、Na2Se2、Li2Se2、Cs2Se2、K2Se2One of (1); the phase transfer catalyst is one of tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate and polyethylene glycol-400;
(2) preparing 26-thio or seleno spirostanol sapogenin:
reacting 26-thio-or seleno-pseudo-spirostanol sapogenin with alkali or a reducing agent in a solvent at 0-150 ℃, and then reacting with acid for 0.1-10 hours to obtain 26-thio-or seleno-spirostanol sapogenin; the molar ratio of the 26-position thio-or seleno-pseudo-spirostanol sapogenin to the alkali is 1.0 (2.0-20.0), and the molar ratio of the 26-position thio-or seleno-pseudo-spirostanol sapogenin to the reducing agent is 1.0 (2.0-5.0); the alkali is organic alkali or inorganic alkali; the acid is an organic acid or an inorganic acid;
(3) preparation of potato trisaccharide donor:
in the presence of an organic solvent and a dehydrating agent, 3, 6-di-oxygen-benzoyl-beta-D-glucosinolate reacts with acyl and silicon-based protected rhamnose trichloroimino ester donor for 1 to 10 hours at the temperature of between 78 ℃ below zero and 40 ℃ by taking Lewis acid or protonic acid as an accelerating agent to obtain potato trisaccharide glucosinolate, and then the potato trisaccharide glucosinolate is hydrolyzed and reacted with trichloroacetonitrile to be converted into trisaccharide trichloroimino ester donor; the mol ratio of the 3, 6-di-oxygen-benzoyl-beta-D-glucothioglycoside to the rhamnose donor and the accelerator is 1.0 (1.0-5.0) to 0.05-0.5; the weight ratio of the 3, 6-di-oxygen-benzoyl-beta-D-glucosinolate to the dehydrating agent is 1.0 (3.0-10.0);
(4) introduction of a 3-position sugar group:
in the presence of an organic solvent and a dehydrating agent, under the conditions of-78-40 ℃, Lewis acid or protonic acid is used as an accelerating agent, 26-position thio or seleno spirost sapogenin reacts with acyl and silicon-based protected glycosyl donor for 1-10 hours, and fully-protected potato trisaccharide is introduced into 3-position OH of the 26-position thio or seleno spirost sapogenin to obtain fully-protected spirost saponin with beta configuration; wherein, the molar ratio of the 26-thio or seleno spirostanol sapogenin to the glycosyl donor and the accelerator is 1.0 (1.0-5.0) to 0.05-0.5; the weight ratio of the 26 th thio or seleno spirostanol sapogenin to the dehydrating agent is 1.0 (3.0-10.0);
(5) synthesis of 26-thio or seleno spirosteroid saponin:
reacting the beta-configuration fully-protected spirostanin with alkali for 10-60 hours at-20-60 ℃ in a solvent, and removing all protecting groups to obtain the beta-configuration 26-thio-or seleno-spirostanin; the alkali is inorganic or organic alkali; the molar ratio of the fully-protected spirostanin to the alkali is 1.0 (0.2-20);
the solvent is organic solvent, water or their mixture;
the above organic solvent is C1- C6Halogenated hydrocarbon of (2), 1, 4-dioxane, C1- C6One or the mixture of alkyl alcohol, diethyl ether, acetonitrile, 2,2, 2-trimethyl acetonitrile, tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, hexamethylphosphoramide, toluene and benzene;
the dehydrating agent is 3A, 4A, 5A molecular sieve or acid-washed 3A molecular sieve or one of anhydrous sodium sulfate, anhydrous calcium sulfate, anhydrous copper sulfate and anhydrous magnesium sulfate or a mixture thereof;
the above inorganic base means a hydroxide, hydride or carbonate of a monovalent metal; the organic base is potassium tert-butoxide, sodium tert-butoxide, tert-butyllithium, sodium methoxide, sodium ethoxide or magnesium methoxide;
the inorganic acid is HCl orH2SO4(ii) a The organic acid is acetic acid or formic acid;
the pseudospirostanol aglycone is pseudodiosgenin [. DELTA. ]5, Y = H, H, 25(R)]。
2. The method of claim 1, wherein the reducing agent is zinc/acetic acid solution or indium/acetic acid or indium/ammonium chloride aqueous solution.
3. The method of claim 1, wherein the lewis acid is one of trialkylsilyl triflate, boron trifluoride etherate, silver triflate, copper triflate, zinc triflate, scandium triflate, lanthanum triflate, ytterbium triflate, indium triflate, trifluoromethanesulfonate, perchloric acid, tetrafluoroboric acid, tetrakis (pentafluorophenyl) borate, or bis (trifluoromethanesulfonyl) imide.
4. The method of claim 1, wherein said acyl group is C2- C8Fatty acyl radicals or C6- C10An aromatic acyl group.
5. The method of claim 3, wherein said trialkylsilyl group is C1- C6Trialkyl silicon base.
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Preparations of heterospirostanols and their pharmacological activities;Hang-Ji Quan et al;《Eur. J. Med. Chem.》;20021231;第37卷;第662页右栏倒数第1段，图2-4,第664-666页, *
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