CN1556111A - 23 position heteroatom substituted analogue of tiger's eye rohdea saponin OSW-1 kind saponin and its synthesis method and use - Google Patents

23 position heteroatom substituted analogue of tiger's eye rohdea saponin OSW-1 kind saponin and its synthesis method and use Download PDF

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CN1556111A
CN1556111A CNA2004100157447A CN200410015744A CN1556111A CN 1556111 A CN1556111 A CN 1556111A CN A2004100157447 A CNA2004100157447 A CN A2004100157447A CN 200410015744 A CN200410015744 A CN 200410015744A CN 1556111 A CN1556111 A CN 1556111A
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glycosyl
osw
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hydroxyl
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CN1247610C (en
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飚 俞
俞飚
史炳锋
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Shanghai Institute of Organic Chemistry of CAS
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    • A—HUMAN NECESSITIES
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    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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Abstract

A new compound of site-23 hetero ornithogalum OSW-saponin, its synthesizing process and its usage are disclosed. Its synthesizing process includes introducing 16 alpha-hydroxy to acetyl dehydro epiandrosterone or its 5,6-bihydrogenated resultant, Aldol reaction to lead-in side chain while creating 17 alpha-hydroxy, oxidizing the hydroxy at site 16 to become ketone, reversing te site-16 hydroxy, glycosidating the hydroxy at site 16, and removing protective radical. Said compound has antineoplastic activity.

Description

Analogue and preparation method and use thereof that 23 heteroatomss of omoto nippoulily saponin OSW-1-1 type saponin replace
Technical field
The present invention relates to have structure and the synthetic method and the purposes of the analogue that 23 heteroatomss of the omoto nippoulily saponin OSW-1-1 type saponin of high antitumor and immunosuppressive activity replace.
Background technology
Omoto nippoulily saponin OSW-1-the 1st, separation and Extraction goes out from a kind of evergreen ornamental plant Herba Phyllanthi Urinariae's (Ornithogalum Saundersiae) who originates in South Africa Swaziland (Swaziland), Transvaal (Transvaal), Natal provinces such as (Natal) underground bulb the saponin with cholestane skeleton [Kubo, S.Y. such as Japanization scholar Sashida; Terao, M.M.; Sashida, Y.Phytochemistry 1992,31, and 3969].Biological activity test shows that OSW-1 has extremely strong broad-spectrum anti-tumor activity [Mimaki, Y.; Kuroda, M.; Kameyama, A.; Sashida, Y.Biorg.Med.Chem.Lett.1997,7,633].Its IC 50Value is between 0.1-0.7nM, than methylamine petrin (methotreate), etoposide (etoposide), Zorubicin (adriamycin), cis-platinum (cisplatin), camptothecine (camptothecin) and the taxol strong 10-100 such as (taxol) of clinical use doubly.And it is to the suitable (IC with clinical application of people's normal lung cytotoxicity 50=1500nM), and the life-span of using the amount of 10mg/Kg can prolong transfection P388 leukemia mouse reach 59%.Usually saponin just has significant hemolytic action (as 10 μ g/mL) under very low concentration, and this hemolytic action has hindered the possibility of saponin as medicine greatly, even and OSW-1 does not still have hemolytic action to HRBC in concentration during up to 100 μ g/mL.In addition, the isolated organ experiment shows that the OSW-1 that is much higher than antitumor dosage does not almost have detrimental effect to endotheliocyte yet.Sashida etc. have isolated a series of from Ornithogalum Saundersiae and corresponding plants and the saponin OSW-1 structurally associated subsequently, and some saponins have shown suitable anti-tumor activity and immunosuppressive activity, and have applied for a series of patents.[(a)Sashita，Y.；Oka，K.；Hirano，T.；Mimaki，Y.；Kuroda，A.；Fujii，A.；Myata，Y.(Sashita?Y.；Oka?K.；Pola?Kasei?Kogyo?Kk，Japan).Jpn.Kokai?Tokkyo?Koho?JP?09048794?A2?18?Feb?1997?Heisei，7?pp.(Japan).(b)Sashita，Y.；Oka，K.；Hirano，T.；Mimaki，Y.；Kuroda，A.；Fujii，A.；Myata，Y.(Sashita?Y.；Oka?K.；PolaKasei?Kogyo?Kk，Japan).Jpn.Kokai?Tokkyo?Koho?JP?09048796?A2?18?Feb?1997?Heisei，6?pp.(Japan).(c)Sashita，Y.；Oka，K.；Hirano，T.；Mimaki，Y.；Kuroda，A.；Fujii，A.；Myata，Y.(SashitaY.；Oka?K.；Pola?Kasei?Kogyo?Kk，Japan).Jpn.Kokai?Tokkyo?Koho?JP?09048795?A2?18?Feb?1997Heisei，7?pp.(Japan).(d)Sashita，Y.；Oka，K.；Hirano，T.；Mimaki，Y.；Kuroda，A.；Fujii，A.；Myata，Y.(Sashita?Y.；Oka?K.；Pola?Kasei?Kogyo?Kk，Japan).Jpn.Kokai?Tokkyo?Koho?JP?09040691?A210?Feb?1997?Heisei，7?pp.(Japan).(e)Sashita，Y.；Oka，K.；Hirano，T.；Mimaki，Y.；Kuroda，A.；Fujii，A.；Myata，Y.(Sashita?Y.；Oka?K.；Pola?Kasei?Kogyo?Kk，Japan).Jpn.Kokai?Tokkyo?KohoJP?09040690?A2?10?Feb?1997?Heisei，10?pp.(Japan).]。
1998, Deng Shaojiang, Yu Biao and Hui Yongzheng etc. took the lead in finishing complete synthesis [Deng, the S. of OSW-1; Yu, B.; Lou, Y.; Hui, Y.J.Org.Chem.1998,202].Complete synthesis report [(a) Morzycki, J.W. arranged again repeatedly for it subsequently; Gryzkiewicz A.Carbohyd.Res.2002,1269-1274. (b) Yu, W.; Jin, Z.J.Am.Chem.Soc.2001,123,3369-3370. (c) Yu, W.; Jin, Z.J.Am.Chem.Soc.2002,124,6576-6583.].In recent years, our group passes through that the chemosynthesis of OSW-1 and derivative thereof and the mensuration of physiologically active have been had further understanding [(a) Ma, X. to its structure activity relationship; Yu, B.; Hui, Y.; Xiao, D.; Ding, J.Carbohydrate Research, 329 (3), 2000,495-505. (b) Ma, X.; Yu, B.; Hui, Y.; Miao, Z.; Ding, J.Carbohydrate Research, 334 (2), 2001,159-164. (c) Ma, X.; Yu, B.; Hui, Y.; Miao, Z.; Ding, J.Bioorganic ﹠amp; Medicinal Chemistry Letters, 11,2001,2153-2156.].
Summary of the invention
The present invention is to provide the new compound of 23 assorted OSW-1 type saponins.
The problem to be solved in the present invention provides a kind of synthetic method of 3 assorted OSW-1 type saponins of Synthetic 2 of practicality.
The problem to be solved in the present invention provides the purposes of 23 assorted OSW-1 type saponins.
The All new compounds general formula of 23 assorted OSW-1 type saponins provided by the invention is as follows:
Wherein: X=O, S, N; R 1=H, (described alkyl is recommended as C to alkyl 1-C 6Alkyl), (described acyl group is recommended as C to acyl group 1-C 10Acyl group) or glycosyl; R 2(described alkyl is recommended as C for=H or alkyl 1-C 3Alkyl), configuration is indefinite; R 3(described alkyl is recommended as C for=straight chain or band branched-chain alkyl 1-C 10Alkyl), when X=N, allow two the replacement; C5-C6 is that singly-bound or two key connect.R 4=glycosyl is recommended as monose or the disaccharides of being with substituted radical.
Above-mentioned R 1During for glycosyl, described glycosyl is recommended as the oligosaccharyl of glucosyl group, mannose group, galactosyl, Arabic glycosyl, xylosyl etc. or their compositions; Above-mentioned R 4Glycosyl in the=glycosyl is the monose or the disaccharides of band substituted radical, and the monose or the substituting group on the disaccharides of described band substituted radical are C 1-C 10Acyl group, described monose or disaccharides are the diglycosyls that glucosyl group, mannose group, galactosyl, Arabic glycosyl, xylosyl etc. or their are formed.
The new compound of described 23 assorted OSW-1 type saponins is for example:
Ac=ethanoyl wherein, MBz=is to anisoyl.
The present invention provides a kind of synthetic method of new practicality of synthetic a series of 23 assorted OSW-1 type saponins first, and this method comprises the steps:
(1) 16 alpha-hydroxy introducing: with acetyl dehydroepiandros-sterone or its 5, the two hydrogenated products of 6-are raw material, introduce 16 α hydroxyls; (2) the Aldol reaction is introduced
Figure A20041001574400081
Side chain shown in the structure makes up simultaneously and obtains 17 Alpha-hydroxies, and wherein X is O or S, R 2, R 3As previously mentioned; (3) 16 hydroxyl oxygens change into ketone; The upset of (4) 16 hydroxyl configurations; The glucosidesization of (5) 16 hydroxyls; (6) remove protecting group and obtain target compound.
The OSW-1 disaccharides that D-wood sugar shown in described 16 glycosyls are recommended as and L-arabinose form: 2-O-(4-anisoyl)-β-D-wood sugar pyrans glycosyl-(1 → 3)-2-O-ethanoyl-α-L-arabopyranose base.
Specifically, recommend each step as follows:
(1) 16 alpha-hydroxy introducing: with acetyl dehydroepiandros-sterone or its 5, the two hydrogenated products of 6-are raw material, and alcohol/bromination ketone refluxes down, and recrystallization obtains 16 alpha-brominated ketone then, 3 hydroxyls of protecting group operation protection, and hydrolysis under the alkaline condition can obtain 16 α hydroxyls.Described alcohol is recommended as methyl alcohol, and hydrolysis is recommended with DMF-H under the described alkaline condition 2O-CH 2Cl 2Make solvent.
(2) side chain is introduced in Aldol reaction (aldol reaction): use ester or thioesters, in the following generation of normal condition 16-hydroxyl steric hindrance inductive Aldol reaction, 17 introducings
Figure A20041001574400082
Side chain shown in the structure makes up simultaneously and obtains 17 Alpha-hydroxies, and wherein X is O or S, R 2, R 3As previously mentioned.Described ester or thioesters are recommended as Ester shown in the structure or thioesters, R 2, R 3As previously mentioned.
(3) 16 hydroxyl oxygens change into ketone: 16 hydroxyls of Swern oxidation or TPAP/NMO oxidation are ketone.The Swem oxidation can be referring to Deng, S.; Yu, B.; Lou, Y.; Hui, Y.J.Org.Chem.1998,202.; The TPAP/NMO oxidation can be referring to Paquette, L. A.; Zhao, M.; Wang, H.L.J.Am.Chem.Soc.1998,120,5213.Described TPAP is Tetrapropylammonium perruthenate, and described NMO is 4-methylmorpholine N-oxide.
The upset of (4) 16 hydroxyl configurations: NaBH 4/ CeCl 37H 216 hydroxyls of reduction upset under the O condition.
The glucosidesization of (5) 16 hydroxyls: use 1 hydroxyl with tribromo-acetyl imines ester activatory glycosyl donor, be recommended as disaccharides and give body, promotor is used the Louis silk acid or the protonic acid of catalytic amount.Described Lewis acid or protonic acid be recommended as the trialkyl silyl triflate (as TMSOTf, TESOTf, TBSOTf) and trifluoromethanesulfonic acid etc.
(6) remove protecting group and obtain target compound, its general structure is as follows:
R in the formula 1, R 2, R 3, R 4, X as previously mentioned.
Be recommended as following general structure:
Wherein: X=O, S, N; R 1=H, alkyl (C 1-C 6), acyl group (C 1-C 10) or glycosyl; R 2=H or alkyl (C 1-C 3), configuration is indefinite; R 3=straight chain or band branched-chain alkyl (C 1-C 10), when X=N, allow two the replacement; C5-C6 is that singly-bound or two key connect.R 4=C 1-C 10Acyl group.
When being N for 23 heteroatomss, step is used DIBAL-H-RNH after (4) 2(or RR ' NHHCl) carries out aminolysis, and the alkyl of R wherein, R '=C1-C10, DIBAL-H are diisobutylaluminiumhydride.Subsequent step is constant.
The novel compound of 23 assorted OSW-1 type saponins provided by the invention shows the very strong inhibition activity to tumour cell, 503nhibiting concentration (IC in activity test in vitro 50) arrival 1-0.01 mcg/ml.503nhibiting concentration (IC as 1 couple of stomach cancer cell AGS of compound, liver cancer cell 7404, breast cancer cell MCF-7 50) be respectively: 2.71,0.027,0.27 mcg/ml; The cis-platinum that is better than comparing (its 503nhibiting concentration is respectively 7.23,2.51,5.61 mcg/ml).
Embodiment
Embodiment 1
23-oxa--OSW-1's (1) is synthetic
Synthetic route is as shown below:
Figure A20041001574400101
Reagent and condition: (a) 3 equivalent CuBr 2, CH 3OH refluxes 99%; (b) TBSCl, imidazole, DMF, room temperature is spent the night, and 96%; (c) 1.3 equivalent NaOH, DMF-H 2O-CH 2Cl 2(v/v=3: 1: 2), room temperature is spent the night, and 94.5%; (d) i) iPr 2NH, nBuLi ,-78 ℃, 15 minutes; Ii) HMPA, THF ,-78 ℃, C 2H 5CO 2CH 2CH (CH 3) 2, 0.5 hour; Iii) 6 ,-78 ℃, 78%; (e) TPAP, NMO, CH 2Cl 2, 4 MS, room temperature is spent the night, 91% or Swern oxidation; (f) NaBH 4, CeCl 37H 2O, THF ,-10 ℃, 81%; (g) 10,0.1 equivalent TMSOTf, 4 MS, CH 2Cl 2,-20 ℃, 2 hours, 49%; (h) Pd (MeCN) 2Cl 2, acetone-water (v/v=20: 1), spend the night, 85.8%. by room temperature
Concrete experiment and data:
(1)16α-Bromo-17-oxo?Steroids?4
Acetyl dehydroepiandros-sterone 3 (16.8 gram) and cupric bromide (34.3 gram) reflux in 400 ml methanol, and after 8 hours, reaction finishes, and cooling is filtered, concentrate to remove partial solvent, and in impouring 200 ml waters, dichloromethane extraction, saturated sodium-chloride washing, anhydrous Na 2SO 4Dry.Filter, be spin-dried for, recrystallizing methanol gets white solid 4 (16.9 grams, 91%).[α] 24 D＝-17.76(c0.8，CHCl 3)； 1H?NMR(300MHz，CDCl 3)：δ5.39-5.37(m，1H)，4.56-4.54(m，1H)，3.56-3.53(m，1H)，1.04(s，3H)，0.93(s，3H)。
(2)16-Bromo-3β-O-(tert-butyldimethylsilyl)-17-oxo?steroids?5：
Compound 4 (3.1 grams, 8.4 mmoles), imidazoles (1.4 grams, 21 mmoles), TBSCl (tert-butyl-dimethylsilyl chloride) (3.8 grams, 12.6 mmoles) is dissolved among 30 milliliters of exsiccant DMF stirred overnight at room temperature, CH 2Cl 2Dilution, washing, 5%HCl, saturated NaHCO 3, saturated NaCl solution washing, anhydrous Na 2SO 4Drying is filtered, and is spin-dried for.Rapid column chromatography (sherwood oil: ethyl acetate: methylene dichloride=34: 2: 1), obtain 16 isomerized white solid product 5 (3.9 grams, 96%). 1H NMR (300MHz, CDCl 3): δ 5.34-5.33 (m, 1H), 4.55-4.53 (m, 1H), 3.52-3.41 (m, 1H), 1.02 (s, 3H), 0.92 (s, 3H), 0.89 (s, 6H), 0.06 (s, 6H); EIMS m/z (%): 425 (isotopic peak, 100), 423 (M-57 +, 94.20); Anal.Calcd for C 25H 41BrO 2Si:C, 62.35; H, 8.58; Found:C, 62.79; H, 8.77.
(3)16α-Hydroxy-3β-O-(tert-butyldimethylsilyl)-17-oxo?steroids?6：
Compound 5 (3.7 grams, 7.68 mmoles) is dissolved in 30 milliliters of CH 2Cl 2In the mixing solutions of 45 milliliters of DMF, NaOH (0.4 gram, 10 mmoles) is dissolved in and drops in the mixture stirred overnight at room temperature in 15 ml waters, the reaction solution washing, saturated NaCl washes, and the organic phase anhydrous sodium sulfate drying filters, be spin-dried for, column chromatography (sherwood oil: ethyl acetate=7: 1), obtain white solid 6 (3.0 grams, 95%).[α] 26 D＝10.40(c1.0，CHCl 3)； 1H?NMR(300MHz，CDCl 3)：5.34-5.32(m，1H)，4.40-4.37(m，1H)，3.53-3.43(m，1H)，1.02(s，3H)，0.97(s，3H)，0.88(s，9H)，0.05(s，6H)；ESIMSm/z：436(M+H 2O +)，459(M+H 2O+Na +)；Anal.Calcd?for?C 25H 42O 3Si：C，71.72；H，10.11；Found：C，71.41；H，10.08。
(4)16，17-cis?Diol?7：
Condition A: in the exsiccant reaction flask, under the argon shield, iPr 2NH (2.8 milliliters) is chilled to-45 ℃ in 40 milliliters of THF, dropwise add n(12 milliliters, 1.6M), constant temperature 10 minutes is chilled to-78 ℃ to BuLi, dropwise adds isobutyl propionate (3.2 milliliters), constant temperature 1 hour.Dropwise add the compound 6 (1 gram) that is dissolved in 10 milliliters of THF ,-78 ° were reacted 3 hours, stopped reaction, and among the HCl that impouring is 60 milliliter 10%, ethyl acetate extraction, saturated NaCl washes, anhydrous sodium sulfate drying.Filter, be spin-dried for, column chromatography (sherwood oil: ethyl acetate=8: 1) get spumescence solid 7 (1.02 grams, 78%).[α] 26 D＝-41.34(c1.0，CHCl 3)； 1HNMR(300?MHz，CDCl 3)：δ5.25(m，1H)，4.18-4.16(m，1H)，3.88-3.84(m，1H)，3.54(br，1H)，3.53-3.41(m，1H)，2.75(q，J＝7.1Hz，1H)，1.23(d，J＝7.1Hz，1H)，1.02(s，3H)，0.97(s，3H)，0.93(s，3H)，0.83(s，9H)，0.75(s，3H)，0.05(s，6H)；EIMS?m/z(％)：548(M +)，491(M +-57)；Anal.Calcd?for?C 30H 52O 5Si：C，69.18；H，10.06；Found：C，69.42；H，10.32。
(5)Ketone?8：
TPAP (47 milligrams, 0.26 equivalent) and NMO (194 milligrams) are dissolved in 5 milliliters of dry CH 2Cl 2In, adding 4 MS, normal temperature adds 7 (348 milligrams), and after 4 hours, diatomite filtration is spin-dried for, column chromatography (sherwood oil: ethyl acetate=60: 1) get white solid 8 (315 milligrams, 91%).[α] 26 D＝-114.4(c1.0，CHCl 3)； 1H?NMR(300MHz，CDCl 3)：δ5.32-5.30(m，1H)，4.04-3.88(m，2H)，3.49(m，1H)，2.58(q，J＝7.2Hz，1H)，1.27(d，J＝7.2Hz，3H)，1.02(s，3H)，0.98(s，3H)，0.96(s，3H)，0.88(s，9H)，0.78(s，3H)，0.05(s，6H)；EIMS?m/z(％)：546(M +，7.53)，489(M-57 +，56.28)；Anal.Calcd?for?C 32H 54O 5Si：C，70.28；H，9.95；Found：C，69.80；H，10.12。
More economical method is operated same ordinary method for using the Swern oxidation.
(6)16，17-trans?Diol?9：
Compound 8 (280 milligrams) is dissolved among 12 milliliters of THF, and-10 ℃ add CeCl down 37H 2O (243 milligrams) and NaBH 4(130 milligrams) after 2 hours, are cooled to-78 ℃, slowly add 0.5 milliliter of CH 3The OH cancellation adds 10 milliliter 5% hydrochloric acid, CH again 2Cl 2Extraction, saturated sodium-chloride is washed, anhydrous sodium sulfate drying.Filter, be spin-dried for, column chromatography (sherwood oil: ethyl acetate=30: 1) get white solid 9 (227 milligrams, 81%).[α] 26 D＝-38.0(c0.9，CHCl 3)； 1H?NMR(300MHz，CDCl 3)：δ5.26-5.24(m，1H)，3.95-3.81(m，3H)，3.50-3.34(m，1H)，3.34(br，1H)，3.05(q，J＝7.1Hz，1H)，1.21(d，J＝7.1Hz，1H)，0.95(s，3H)，0.90(s，3H)，0.88(s，3H)，0.85(s，3H)，0.83(s，9H)，0.05(s，6H)；EIMS?m/z(％)：530(M-18 +)，473(M-57-18 +)；Anal.Calcd?for?C 32H 56O 5Si：C，70.02；H，10.28；Found：C，69.87；H，10.28。
(7) the 23-oxa--OSW-1 11 of full guard:
9 (150 milligrams, 0.27 mmole) and 10 (1.69 grams, 6.4 equivalents), 4 MS are in 30 milliliters of exsiccant CH 2Cl 2In, stirring at room 15 minutes is chilled to-20 ℃, 3 milliliters of TMSOTf (trimethylsilyltrifluoromethane sulfonate) (CH of 0.0045M 2Cl 2Liquid) dropwise add, after 3 hours, 2.5 milliliters of Et 3The N cancellation is filtered, and is spin-dried for column chromatography (sherwood oil: ethyl acetate=30: 1-25: 1) get 11 (183 milligrams, 49%).[α] 20 D＝-38.3(c1.1，CHCl 3)； 1H?NMR(300MHz，CDCl 3)：δ8.06?and?6.89(AB，4H)，5.30(m，1H)，4.98(br，1H)，4.90-4.89(m，1H)，4.81-4.80(1H)，4.39-4.35(1H)，4.30(br，1H)，3.86(s，3H)，2.87(q，J＝7.4Hz，3H)，2.00(s，3H)，1.17(d，J＝7.4Hz，1H)，0.06(s，6H)； 13C?NMR(75?MHz，CDCl 3)：δ179.3，168.9，164.6，163.3，141.5，132.0，122.8，121.1，113.3，100.5，84.872.6，71.3，70.6，69.4，55.4，53.3，49.6，48.3，45.8，42.8，40.9，37.3，36.6，34.9，32.0，29.6，27.5，25.9，20.7，20.5，19.2，18.9，18.7，18.2，14.0，13.0，6.9，6.7，4.8，4.7，-4.6；MALDI-MS?m/z：1353.7(M+Na +)；HRMS(MALDI)m/z?1353.7702(M+Na +)Calcd?for?C 70H 122NaO 16Si 4：1353.7724。
(8) 23-oxa--OSW-1 1:
Compound 11 (41 milligrams, 0.029 mmole) and about 3 milligrams of PdCl 2(CH 3CN) 2(v/v=20: 1), stirred overnight at room temperature is spin-dried for, column chromatography (methylene dichloride: methyl alcohol=25: 1) get white solid 1 (23 milligrams, 86%) to be dissolved in 2 milliliters of acetone and water.[α] 20 D＝-47.2(c1.2，CHCl 3)； 1H?NMR(300MHz，Py-d 5)：δ8.40?and?7.14(AB，4H)，5.82-5.75(2H)，5.46(m，1H)，5.30(d，J＝7.0Hz，1H)，4.67(d，J＝6.3Hz，1H)，4.63(s，1H)，4.51-4.25(8H)，3.81(s，3H)，3.27(q，J＝7.5Hz，1H)，2.01(s，3H)，1.55(d，J＝7.5Hz，3H)，1.13(s，3H)，1.02(s，3H)，0.88(d，J＝7.5Hz，6H)； 13C?NMR(75MHz，Py-d 5)：δ178.2，169.4，165.3，163.6，141.7，132.2，120.9，113.8，102.5，101.8，88.2，84.8，79.4，76.2，75.4，74.6，71.0，70.4，70.2，67.7，66.3，65.5，55.3，50.0，48.7，46.3，43.3，41.1，37.6，36.6，35.6，32.5，32.4，32.0，31.9，29.8，27.8，20.7，20.6，19.4，19.0，18.9，13.3，13.2；MALDI-MS?m/z：897.4(M+Na +)；HRMS(MALDI)m/z?897.4243(M+Na +)Calcd?for?C 46H 66O 16Na：897.4279。
Embodiment 2
23-azepine-OSW-12's is synthetic
Synthetic route is as shown below:
Reagent and condition: (a) 3 equivalent CuBr 2, CH 3OH refluxes 99%; (b) TBSCl, imidazole, DMF, room temperature is spent the night, and 96%; (c) 1.3 equivalent NaOH, DMF-H 2O-CH 2Cl 2(v/v=3: 1: 2), room temperature is spent the night, and 94.5%; (d) i) iPr 2NH, nBuLi ,-78 ℃, 15 minutes; Ii) HMPA, THF ,-78 ℃, C 2H 5CO 2CH 2CH (CH 3) 2, 0.5 hour; Iii) 6 ,-78 ℃, 78%; (e) TPAP, NMO, CH 2Cl 2, 4 MS, room temperature is spent the night, and 91%; Or Swern oxidation; (f) NaBH i) 4, CeCl 37H 2O, THF ,-10 ℃; Ii) CH 3OH, room temperature, 10 minutes, then water, room temperature, 0.5 hour, 92%. or condition f '; I) NaBH 4, CeCl 37H 2O, THF ,-10 ℃; Ii) CH 3OH ,-78 ℃, 0.5 hour, then H 2O is to room temperature (g) i) iBuNH 2, THF, DIBAL-H, 0 ℃, 2 hours; Ii) 14 (or 14 '), THF, room temperature, 4 hours, 95%; (h) 10,0.1 equivalent TMSOTf, 4 MS, CH 2Cl 2,-20 ℃, 2 hours, 65%; (i) Pd (MeCN) 2Cl 2, acetone-water (v/v=20: 1), room temperature is spent the night, and 75%.
Concrete experiment and data:
(1)16，17-cis?Diol?12：
Reaction conditions is with above-mentioned Condition A, get white solid 12 (1.94 grams, 75%), 21-methyl isomer (0.31 gram, 12%).[α] 26 D＝-45.47(c1.0，CHCl 3)； 1H?NMR(300MHz，CDCl 3)：δ5.30-5.28(m，1H)，4.19-4.11(m?&?q，1H+2H)，3.70-3.50(br，1H)，3.53-3.44(m，1H)，2.78(q，J＝7.1Hz，1H)，1.31-1.25(d?&?t，6H)，0.99(s，3H)，0.88(s，9H)，0.80(s，3H)，0.05(s，6H)；EIMS?m/z(％)：518(M +，5.36)，561(M-57 +，100)；Anal.Calcd?forC 30H 52O 5Si：C，69.18；H，10.06；Found：C，69.12；H，9.67。
(2)16-Ketone?13：
TPAP (221 milligrams, 0.2 equivalent) and NMO (1.14 grams, 3 equivalents) are dissolved in 30 milliliters of dry CH 2Cl 2In, adding 4 MS, normal temperature adds 12 (1.64 grams), and after 4 hours, diatomite filtration is spin-dried for, column chromatography (sherwood oil: ethyl acetate=30: 1) get white solid 13 (1.49 grams, 92%).[α] 26 D＝-126.8(c1.0，CHCl 3)； 1H?NMR(300MHz，CDCl 3)：δ5.32-5.30(m，1H)，4.28-4.20(m，2H)，3.53-3.46(m，1H)，2.56(q，J＝7.1Hz，1H)，1.33(t，J＝7.1Hz，3H)，1.26(d，J＝7.1Hz，3H)，1.02(s，3H)，0.89(s，6H)，0.78(s，3H)，0.06(s，6H)；EIMS?m/z(％)：520(M +)，463(M-57 +，100)；Anal.Calcd?for?C 30H 50O 5Si：C，69.45；H，9.71；Found：C，69.20；H，9.74。
More economical method is operated same ordinary method for using the Swern oxidation.
(2)Lactone?14：
Compound 13 (318 milligrams, 19 mmoles), NaBH 4(160 milligrams, 135 mmoles) and CeCl 37H 2O (320 milligrams, 27 mmoles) is suspended among 15 milliliters of exsiccant THF, and 0 ℃ was reacted 1 hour down, adds 1 milliliter of CH 3OH, stirring at room 10 minutes adds 1 ml water again, stirring at room half an hour, methylene dichloride dilution, washing, anhydrous sodium sulfate drying.Filter, be spin-dried for, column chromatography (sherwood oil: ethyl acetate: methylene dichloride=9: 1: 2) get white solid 14 (267 milligrams, 92%).[α] 26 D＝-85.23(c0.3，CHCl 3)； 1H?NMR(400MHz，CDCl 3)：δ5.27-5.25(m，1H)，4.43(dd，J＝4.7Hz，3.2，1H)，3.46-3.39(m，1H)，2.67(q，J＝7.7Hz，1H)，1.29(d，J＝7.7Hz，3H)，1.03(s，3H)，0.89(s，9H)，0.81(s，3H)，0.06(s，6H)；ESIMS?m/z：492.4(M+Na +)，971.6(2M+Na +)；Anal.Calcd?for?C 28H 46O 4Si：C，70.84；H，9.77；Found：C，71.03；H，9.78。
(4)Amide?15：
DIBAL-H- iBuNH 2The preparation of mixture: 0 ℃, under the argon shield, 4.9mL DIBAL-H (1Min toluene) dropwise adds 0.5 milliliter iBuNH 2Among 2 milliliters of THF of (5 mmole), after adding, rise to room temperature, stirred 2 hours, make the solution that concentration is about 0.72mol/L.
30 milligrams of compounds 14 are dissolved among 2 milliliters of anhydrous THF, under the argon shield room temperature, dropwise add the DIBAL-H-of 0.44 milliliter (0.72mol/L, 5 equivalents) iBuNH 2Mixture, after the TLC detection reaction was finished, 0.1 ml water cancellation added 5 milliliters of 1M KHSO 4Stir, dichloromethane extraction, the saturated common salt washing, the organic phase anhydrous sodium sulfate drying filters, and is spin-dried for rapid column chromatography (sherwood oil: ethyl acetate=5: 1) get white solid (33 milligrams, 95%).Can compound 14 ' be feedstock production also, operate identical.[α] 20 D＝-39.2(c0.5，CHCl 3)； 1H?NMR(300MHz，CDCl 3)：δ5.77(br，1H)，5.29-5.28(m，1H)，4.21(s，1H)，3.92(m，1H)，3.50-3.43(m，1H)，3.12-3.00(m，2H)，2.86(q，J＝7.2Hz，1H)，2.66(m，1H)，1.24(d，J＝7.2Hz，3H)，1.13(s，3H)，0.98(s，3H)，0.91(s，3H)，0.88(d，9H)； 13C?NMR(75MHz，CDCl 3)：δ178.4，141.5，120.8，85.1，81.8，72.5，49.6，48.4，46.7，46.3，42.7，41.8，37.3，36.5，35.8，32.6，32.0，31.9，31.8，28.5，25.9，20.4，20.1，19.4，18.2，13.4，-4.6；ESI-MS?m/z：570.4(M+Na +)；HRMS(ESI)m/z570.3963(M+Na) +Calcd?for?C 32H 57NO 4SiNa +：570.3949。
(5) the 23-azepine-OSW-1 16 of full guard:
15 (33 milligrams, 0.06 mmole) and 10 (70 milligrams, 0.072 mmole), 200 milligram of 4 MS is in 3 milliliters of exsiccant CH 2Cl 2In, stirring at room 15 minutes is chilled to-20 ℃, the 30 microlitre TMSOTf (CH of 0.1M 2Cl 2Liquid) dropwise add, after 2 hours, 0.1 milliliter of Et 3The N cancellation is filtered, and is spin-dried for column chromatography (sherwood oil: ethyl acetate=15: 1-10: 1) get 16 (52 milligrams, 65%).[α] 20 D＝-24.3(c1.6，CHCl 3)； 1H?NMR(300MHz，CDCl 3)：δ8.03?and?6.93(AB，4H)，7.20(m，1H)，5.62(s，1H)，5.30(m，1H)，4.89(s，1H)，4.82-4.81(m，2H)，4.47-4.42(2H)，3.89(s，3H)，3.50-3.47(m，1H)，3.12(q，J＝7.4Hz，1H)，1.99(s，3H)，1.32(d，J＝7.4Hz，3H)，0.06(s，6H)；δ180.1，169.1，166.7，163.4，141.3，132.0，122.0，121.1，113.6，100.5，98.1，91.2，85.5，76.1，73.9，72.5，71.9，70.6，68.4，65.3，63.2，59.7，55.5，49.6，48.2，46.1，45.7，42.9，40.4，37.2，36.5，35.0，32.3，32.1，31.9，28.2，25.9，20.7，20.6，20.2，20.1，19.2，18.2，14.5，14.4，6.9，6.7，5.1，5.0，4.7，-4.6；MALDI-MS?m/z：1352.7(M+Na +)；HRMS(MALDI)m/z?1352.7905(M+Na) +Calcd?for?C 70H 123NaNO 15Si 4：1352.7862。
(6) 23-azepine-OSW-1 2:
Compound 16 (40 milligrams, 0.03 mmole) and about 2 milligrams of PdCl 2(CH 3CN) 2(v/v=20: 1), stirred overnight at room temperature is spin-dried for, column chromatography (methylene dichloride: methyl alcohol=25: 1) get white solid 2 (20 milligrams, 75%) to be dissolved in 2 milliliters of acetone and water.[α] 20 D＝-45.3(c0.9，CHCl 3)； 1H?NMR(300MHz，CDCl 3)：δ8.07?and?6.99(AB，4H)，5.65-5.62(m，1H)，5.32-5.31(m，1H)，5.27(s，1H)，4.90(br，1H)，4.90-4.87(m，1H)，4.71-4.70(m，1H)，4.39(br，1H)，4.32-4.31(m，1H)，4.28-4.27(m，1H)，3.96(br，1H)，3.88(s，3H)，2.58(q，J＝7.4Hz，1H)，2.02(s，3H)，1.19(d，J＝7.4Hz，3H)，1.00(s，3H)，0.84(s，3H)，0.79(d，J＝6.6Hz，6H)； 13C?NMR(75MHz，CDCl 3)：δ179.4，169.6，166.0，164.3，140.5，132.2，121.6，121.0，114.2，99.5，99.4，90.4，85.3，76.1，72.6，72.4，71.7，70.3，69.1，63.7，63.0，59.6，55.6，49.5，48.0，46.2，45.7，42.3，40.6，37.1，36.4，34.7，32.2，31.8，31.6，28.2，20.8，20.6，20.0，19.9，19.4，14.5，13.5；MALDI-MS?m/z：896.5(M+Na +)；HRMS(MALDI)m/z?896.4446(M+Na +)Calcd?for?C 46H 67O 15NaN：896.4403。

Claims (10)

1. 23 assorted OSW-1 analogues is characterized in that this structure is as follows:
(1) 3 is that hydroxyl or hydroxyl are replaced by alkyl, acyl group or glycosyl; (2) 21 is hydrogen or alkyl, and configuration is indefinite; (3) 23 heteroatomss replace, and comprise N, S, O; Connecting substituting group on (4) 23 heteroatomss is alkyl, when 23 heteroatomss are N, allows two alkyl to replace; (5) 16 glycosyls for the connection of β hydroxyl; (6) 5 of steroidals are connected for singly-bound or two key with 6.
Its general structure is as follows:
Figure A2004100157440002C1
Wherein: X=O, S, N; R 1=H, alkyl, acyl group or glycosyl; R 2=H or alkyl, configuration is indefinite; R 3=straight chain or band branched-chain alkyl when X=N, allow two the replacement; C5-C6 is that singly-bound or two key connect R 4=glycosyl, described glycosyl is the monose or the disaccharides of band substituted radical.
2. 23 assorted OSW-1 analogues as claimed in claim 1 is characterized in that described R 1=H, C 1-C 6Alkyl, C 1-C 10Acyl group or glycosyl, described glycosyl is the oligosaccharyl that glucosyl group, mannose group, galactosyl, Arabic glycosyl, xylosyl etc. or their are formed; R 2=H or C 1-C 3Alkyl, R 3=C 1-C 10Straight chain or the band branched-chain alkyl; Wherein the glycosyl in the glycosyl of 16 β hydroxyl connections is the monose or the disaccharides of band substituted radical, and the monose or the substituting group on the disaccharides of described band substituted radical are C 1-C 10Acyl group, described monose or disaccharides are the diglycosyls that glucosyl group, mannose group, galactosyl, Arabic glycosyl, xylosyl etc. or their are formed.
3. 23 assorted OSW-1 analogues as claimed in claim 1 is characterized in that described 16 glycosyl R 4For
Figure A2004100157440003C1
The disaccharides that D-wood sugar shown in the structure and L-arabinose form: 2-O-acyl group-β-D-wood sugar pyrans glycosyl-(1 → 3)-2-O-ethanoyl-α-L-arabopyranose base, acyl group R wherein 5Be C 1-C 10Acyl group, be recommended as single the replacement or polysubstituted aromatic ester.
4. the synthetic method of the practicality of a kind of 23 assorted OSW-1 as claimed in claim 1 is characterized in that this method comprises the steps:
(1) 16 alpha-hydroxy introducing: with acetyl dehydroepiandros-sterone or its 5, the two hydrogenated products of 6-are raw material, introduce 16 α hydroxyls; (2) the Aldol reaction is introduced Side chain shown in the structure makes up simultaneously and obtains 17 Alpha-hydroxies, and wherein X is O or S, R 2, R 3According to claim 1; (3) 16 hydroxyl oxygens change into ketone; The upset of (4) 16 hydroxyl configurations; The glucosidesization of (5) 16 hydroxyls; (6) remove protecting group and obtain target compound.
When X=N, step (4) back adds aminolysis reaction, and is follow-up constant.
5. synthetic method as claimed in claim 4 is characterized in that X=O in described 23 assorted OSW-1 structures, and during S, each step is as follows:
(1) 16 alpha-hydroxy introducing: with acetyl dehydroepiandros-sterone or its 5, the two hydrogenated products of 6-are raw material, and methyl alcohol/bromination ketone refluxes down, and recrystallization obtains 16 alpha-brominated ketone then, 3 hydroxyls of protecting group operation protection, DMF-H 2O-CH 2Cl 2Do hydrolysis under the solvent alkaline condition, can obtain 16 α hydroxyls.
(2) side chain is introduced in the Aldol reaction: use ester or thioesters, in the following generation 16 Alpha-hydroxy steric hindrance inductive Aldol reaction of normal condition, 17 introducings Side chain shown in the structure makes up simultaneously and obtains 17 Alpha-hydroxies, and wherein X is O or S, R 2, R 3According to claim 1.
(3) 16 hydroxyl oxygens change into ketone: 16 hydroxyls of Swern oxidation or TPAP/NMO oxidation are ketone.。
The upset of (4) 16 hydroxyl configurations: NaBH 4/ CeCl 37H 216 hydroxyls of reduction upset under the O condition.
The glucosidesization of (5) 16 hydroxyls: use 1 hydroxyl tribromo-acetyl imines ester activatory glycosyl donor, promotor is used the Louis silk acid or the protonic acid of catalytic amount.
(6) remove protecting group and obtain target compound, its general structure according to claim 1.
6. synthetic method as claimed in claim 4 is characterized in that described 3 are hydroxyl, 16 glycosyl R 4For
Figure A2004100157440004C1
The disaccharides that D-wood sugar shown in the structure and L-arabinose form: 2-O-acyl group R 5-β-D-wood sugar pyrans glycosyl-(1 → 3)-2-O-ethanoyl-α-L-arabopyranose base, acyl group R wherein 5Be C 1-C 10Acyl group.
7. synthetic method as claimed in claim 4 is characterized in that 16 hydroxyl inductive Aldol reactions are adopted in the introducing of 17 side chains.
8. synthetic method as claimed in claim 4 is characterized in that each step is as follows when X is N in described 23 assorted OSW-1 structures:
Step (1), (2), (3), (4) be with the described step of claim 4 (1), and (2), (3), (4) are to the compound DIBAL-H-RNH of the 23-oxa-that obtains 2Perhaps RR ' NHHCl carries out aminolysis, and wherein R, R ' are C 1-C 10Alkyl.Subsequent operations is with the described step of claim 4 (5), (6).
9. synthetic method as claimed in claim 8 is characterized in that 23-oxa-compound or its product that lactonizes are adopted aminolysis Synthetic 2 3-azepine-OSW-1.
10. the purposes of 23 assorted OSW-1 analogues as claimed in claim 1 is characterized in that being used to prepare the medicine that suppresses tumour.
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CN100343273C (en) * 2005-10-28 2007-10-17 中国科学院上海有机化学研究所 C17-hydroxy-steroid lactone antitumour medicine
CN101029070B (en) * 2006-12-14 2010-05-19 上海中药创新研究中心 Preparation of omoto nippoulily saponin OSW-1
CN101089008B (en) * 2007-06-01 2010-05-19 中国科学院上海有机化学研究所 Dicyclic analog without ring A and ring B of omithogalum caudatum OSW-1 saponin and its synthesis process and use

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PL214648B1 (en) 2009-02-09 2013-08-30 Univ W Bialymstoku Analogues of OSW-1 saponine with simplified structure
CN109430059A (en) * 2018-12-25 2019-03-08 云南省农业科学院花卉研究所 A kind of cut-flower Ornithogalum caudatum in vitro culture quick-breeding method

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CN100343273C (en) * 2005-10-28 2007-10-17 中国科学院上海有机化学研究所 C17-hydroxy-steroid lactone antitumour medicine
CN101029070B (en) * 2006-12-14 2010-05-19 上海中药创新研究中心 Preparation of omoto nippoulily saponin OSW-1
CN101089008B (en) * 2007-06-01 2010-05-19 中国科学院上海有机化学研究所 Dicyclic analog without ring A and ring B of omithogalum caudatum OSW-1 saponin and its synthesis process and use

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