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【结 构 式】 
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【药物名称】Oleanolic acid 【化学名称】3beta-Hydroxyolean-12-en-28-oic acid 【CA登记号】508-02-1 【 分 子 式 】C30H48O3 【 分 子 量 】456.71526 |
【开发单位】Regional Research Laboratory, Jammu-Tawi (Originator) 【药理作用】Antiinflammatory Drugs |
合成路线1
The dihydroxylation of the farnesyl acetate (I) with Noe-Lin catalyst gives the dihydroxy compound (II), which is converted to the epoxide (III) by treatment first with mesyl chloride and pyridine, and then with K2CO3 in methanol. The reaction of (III) with mesyl chloride and LiBr in THF yields the bromide (IV), which is condensed with the silylated amine (V) by means of LDA in AcOH / NaOAc affording the epoxidized acyl silane (VI). The condensation of (VI) with isopropenyllithium (VII) and the cyclohexenylmethyl bromide (VIII) by means of BaI2 in THF gives the precursor (IX), which is cyclized by means of MeAlCl2 and protected with TBDMS-Cl in dichloromethane yielding the tricyclic ketone (X). The reaction of (X) with Tf2N-Ph affords the enol triflate (XI), which is further cyclized by means of Me3Sn-SnMe3 and palladium tetrakis(triphenylphosphine) in refluxing THF giving the silylated pentacyclic alcohol (XII), which is desilylated with TBAF in THF affording the pentacyclic alcohol (XIII). The benzoylation of (XIII) with benzoyl chloride gives benzoate (XIV), which is selectively methylenated with CH2I2 and Br2Zn in toluene yielding the cyclopropanated compound (XV).
| 【1】 Huang, A.X.; Corey, E.J.; Xiong, Z.; An exceptionally short and simple enantioselective total synthesis of pentacyclic triterpenes of the beta-amyrin family. J Am Chem Soc 1999, 121, 43, 9999. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 35270 | (2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrienyl acetate | 29548-30-9 | C17H28O2 | 详情 | 详情 |
| (II) | 35271 | (2E,6E,10R)-10,11-dihydroxy-3,7,11-trimethyl-2,6-dodecadienyl acetate | C17H30O4 | 详情 | 详情 | |
| (III) | 35272 | (2E,6E)-9-[(2S)-3,3-dimethyloxiranyl]-3,7-dimethyl-2,6-nonadien-1-ol | C15H26O2 | 详情 | 详情 | |
| (IV) | 35273 | (3S)-3-[(3E,7E)-9-bromo-3,7-dimethyl-3,7-nonadienyl]-2,2-dimethyloxirane | C15H25BrO | 详情 | 详情 | |
| (V) | 35274 | N-[(Z)-1-[tert-butyl(dimethyl)silyl]ethylidene]-1-methoxy-2-propanamine; N-[(Z)-1-[tert-butyl(dimethyl)silyl]ethylidene]-N-(2-methoxy-1-methylethyl)amine | C12H27NOSi | 详情 | 详情 | |
| (VI) | 35275 | (4E,8E)-1-[tert-butyl(dimethyl)silyl]-11-[(2S)-3,3-dimethyloxiranyl]-5,9-dimethyl-4,8-undecadien-1-one | C23H42O2Si | 详情 | 详情 | |
| (VII) | 35276 | isopropenyllithium | C3H5Li | 详情 | 详情 | |
| (VIII) | 35277 | 2-bromo-1-(bromomethyl)-4,4-dimethyl-1-cyclohexene | C9H14Br2 | 详情 | 详情 | |
| (IX) | 35278 | ([(4E,8E)-1-[(Z)-3-(2-bromo-4,4-dimethyl-1-cyclohexen-1-yl)-1-methylpropylidene]-11-[(2S)-3,3-dimethyloxiranyl]-5,9-dimethyl-4,8-undecadienyl]oxy)(tert-butyl)dimethylsilane; (4E,8E)-1-[(Z)-3-(2-bromo-4,4-dimethyl-1-cyclohexen-1-yl)-1-methylpropylidene]-11-[(2S)-3,3-dimethyloxiranyl]-5,9-dimethyl-4,8-undecadienyl tert-butyl(dimethyl)silyl ether | C35H61BrO2Si | 详情 | 详情 | |
| (X) | 35279 | (1S,4aR,4bR,7S,8aR,10aR)-1-[2-(2-bromo-4,4-dimethyl-1-cyclohexen-1-yl)ethyl]-7-[[tert-butyl(dimethyl)silyl]oxy]-1,4b,8,8,10a-pentamethyldodecahydro-2(1H)-phenanthrenone | C35H61BrO2Si | 详情 | 详情 | |
| (XI) | 35280 | (1S,4aR,4bR,7S,8aR,10aR)-1-[2-(2-bromo-4,4-dimethyl-1-cyclohexen-1-yl)ethyl]-7-[[tert-butyl(dimethyl)silyl]oxy]-1,4b,8,8,10a-pentamethyl-1,4,4a,4b,5,6,7,8,8a,9,10,10a-dodecahydro-2-phenanthrenyl trifluoromethanesulfonate | C36H60BrF3O4SSi | 详情 | 详情 | |
| (XII) | 35281 | (3S,4aR,6aR,6bS,14aR,14bR)-4,4,6a,6b,11,11,14b-heptamethyl-1,2,3,4,4a,5,6,6a,6b,7,8,9,10,11,12,14,14a,14b-octadecahydro-3-picenyl tert-butyl(dimethyl)silyl ether; [[(3S,4aR,6aR,6bS,14aR,14bR)-4,4,6a,6b,11,11,14b-heptamethyl-1,2,3,4,4a,5,6,6a,6b,7,8,9,10,11,12,14,14a,14b-octadecahydro-3-picenyl]oxy](tert-butyl)dimethylsilane | C35H60OSi | 详情 | 详情 | |
| (XIII) | 35282 | (3S,4aR,6aR,6bS,14aR,14bR)-4,4,6a,6b,11,11,14b-heptamethyl-1,2,3,4,4a,5,6,6a,6b,7,8,9,10,11,12,14,14a,14b-octadecahydro-3-picenol | C29H46O | 详情 | 详情 | |
| (XIV) | 35283 | (3S,4aR,6aR,6bS,14aR,14bR)-4,4,6a,6b,11,11,14b-heptamethyl-1,2,3,4,4a,5,6,6a,6b,7,8,9,10,11,12,14,14a,14b-octadecahydro-3-picenyl benzoate | C36H50O2 | 详情 | 详情 | |
| (XV) | 35284 | C37H52O2 | 详情 | 详情 |
合成路线2
Elimination of the benzoyl group of (XV) with DIBAL in dichloromethane affords alcohol (XVI), which is silylated with TBDMS-Cl and imidazole in DMF giving the silyl ether (XVII). Cleavage of the cyclopropane ring of (XVII) with tert-butyl perbenzoate, followed by hydrolysis of the resulting ester yields the methanol derivative (XVIII), which is selectively reduced with Li in THF/NH3 affor-ding the cis-isomer (XIX). Finally, this compound is oxidized with NaClO4 in tert-butanol and desilylated with tetrabutylammonium fluoride.
| 【1】 Huang, A.X.; Corey, E.J.; Xiong, Z.; An exceptionally short and simple enantioselective total synthesis of pentacyclic triterpenes of the beta-amyrin family. J Am Chem Soc 1999, 121, 43, 9999. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XV) | 35284 | C37H52O2 | 详情 | 详情 | ||
| (XVI) | 35285 | C30H48O | 详情 | 详情 | ||
| (XVII) | 35286 | C36H62OSi | 详情 | 详情 | ||
| (XVIII) | 35287 | [(6aS,6bR,8aR,10S,12aR,12bR)-10-[[tert-butyl(dimethyl)silyl]oxy]-2,2,6a,6b,9,9,12a-heptamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b-hexadecahydro-4(2H)-picenyl]methanol | C36H62O2Si | 详情 | 详情 | |
| (XIX) | 35288 | [(6aS,6bR,8aR,10S,12aR,12bR,14bS)-10-[[tert-butyl(dimethyl)silyl]oxy]-2,2,6a,6b,9,9,12a-heptamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydro-4(2H)-picenyl]methanol | C36H64O2Si | 详情 | 详情 |
合成路线3
The methylation of 7-methoxy-1-tetralone (I) with methyl iodide and potassium tert-butoxide in THF gives the 2,2-dimethyl derivative (II), which is reduced with NaBH4 and acetylated with acetyl chloride yielding the acetate (III). The reduction of (III) with diethylborohydride in TFA affords 7-methoxy-2,2-dimethyltetraline (IV), which is submitted to a Birch reduction with Li/NH3 in THF affording 2,2-dimethyl-7-methoxy-1,2,3,4,5,8-hexahydronaphthalene (V). The condensation of (V) with homofarnesyl iodide (VI) by means of BuLi in THF gives intermediate (VII), which is treated with 2-sulfanylethanol and TFA yielding the ketone (VIII). The reaction of (VIII) with KHMDS and Tf2N-Ph in THF affords the enol triflate (IX), which is selectively brominated with N-bromosuccinimide (NBS) in THF giving the bromohydrine (X). The epoxidation of (X) with K2CO3 in methanol, followed by methylation with Me2CuLi in THF yields the epoxide (XI), which is treated with SiF4 and TFA to afford the fluoroketone (XII). The stereocontroled reduction of the ketone group of (XII) with a chiral oxaazaborolidine (OABL) gives the chiral alcohol (XIII), which is epoxidized by means of sodium isopropoxide in isopropanol yielding the chiral epoxide (XIV).
| 【1】 Corey, E.J.; Lee, J.; Enantioselective total synthesis of oleanolic acid, erythrodiol, beta-amyrin, and other pentacyclic triterpenes from a common intermediate. J Am Chem Soc 1993, 115, 8873. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 21385 | 7-methoxy-3,4-dihydro-1(2H)-naphthalenone | 6836-19-7 | C11H12O2 | 详情 | 详情 |
| (II) | 35723 | 7-methoxy-2,2-dimethyl-3,4-dihydro-1(2H)-naphthalenone | C13H16O2 | 详情 | 详情 | |
| (III) | 35724 | 7-methoxy-2,2-dimethyl-1,2,3,4-tetrahydro-1-naphthalenyl acetate | C15H20O3 | 详情 | 详情 | |
| (IV) | 35725 | 7-methoxy-2,2-dimethyl-1,2,3,4-tetrahydronaphthalene; 7,7-dimethyl-5,6,7,8-tetrahydro-2-naphthalenyl methyl ether | C13H18O | 详情 | 详情 | |
| (V) | 35726 | 7,7-dimethyl-1,4,5,6,7,8-hexahydro-2-naphthalenyl methyl ether; 7-methoxy-2,2-dimethyl-1,2,3,4,5,8-hexahydronaphthalene | C13H20O | 详情 | 详情 | |
| (VI) | 35727 | (6E,10E)-13-iodo-2,6,10-trimethyl-2,6,10-tridecatriene | C16H27I | 详情 | 详情 | |
| (VII) | 35728 | 7-methoxy-2,2-dimethyl-8-[(3E,7E)-4,8,12-trimethyl-3,7,11-tridecatrienyl]-1,2,3,4,5,8-hexahydronaphthalene; 7,7-dimethyl-1-[(3E,7E)-4,8,12-trimethyl-3,7,11-tridecatrienyl]-1,4,5,6,7,8-hexahydro-2-naphthalenyl methyl ether | C29H46O | 详情 | 详情 | |
| (VIII) | 35729 | 7,7-dimethyl-1-[(3E,7E)-4,8,12-trimethyl-3,7,11-tridecatrienyl]-3,4,5,6,7,8-hexahydro-2(1H)-naphthalenone | C28H44O | 详情 | 详情 | |
| (IX) | 35730 | 7,7-dimethyl-1-[(3E,7E)-4,8,12-trimethyl-3,7,11-tridecatrienyl]-3,4,5,6,7,8-hexahydro-2-naphthalenyl trifluoromethanesulfonate | C29H43F3O3S | 详情 | 详情 | |
| (X) | 35731 | 1-[(3E,7E)-11-bromo-12-hydroxy-4,8,12-trimethyl-3,7-tridecadienyl]-7,7-dimethyl-3,4,5,6,7,8-hexahydro-2-naphthalenyl trifluoromethanesulfonate | C29H44BrF3O4S | 详情 | 详情 | |
| (XI) | 35732 | 3-[(3E,7E)-3,7-dimethyl-10-(2,7,7-trimethyl-3,4,5,6,7,8-hexahydro-1-naphthalenyl)-3,7-decadienyl]-2,2-dimethyloxirane | C29H46O | 详情 | 详情 | |
| (XII) | 35733 | (6E,10E)-2-fluoro-2,6,10-trimethyl-13-(2,7,7-trimethyl-3,4,5,6,7,8-hexahydro-1-naphthalenyl)-6,10-tridecadien-3-one | C29H45FO | 详情 | 详情 | |
| (XIII) | 35734 | (3S,6E,10E)-2-fluoro-2,6,10-trimethyl-13-(2,7,7-trimethyl-3,4,5,6,7,8-hexahydro-1-naphthalenyl)-6,10-tridecadien-3-ol | C29H47FO | 详情 | 详情 | |
| (XIV) | 35735 | (3S)-3-[(3E,7E)-3,7-dimethyl-10-(2,7,7-trimethyl-3,4,5,6,7,8-hexahydro-1-naphthalenyl)-3,7-decadienyl]-2,2-dimethyloxirane | C29H46O | 详情 | 详情 |
合成路线4
The cyclization of (XIV) by means of MeAlCl2 in dichloromethane followed by benzoylation with benzoyl chloride gives a mixture of benzoates (XV) and (XVI) that are separated by chromatography. The desired isomer (XV) (additional (XV) is obtained by isomerization of (XVI) by HCl in hot acetic acid) was selctively methylenated with CH2I2 and Br2Zn in toluene yielding the cyclopropanated compound (XVII). Elimination of the benzoyl group of (XVII) with DIBAL in dichloromethane affords alcohol (XVIII), which is silylated with TBDMS-Cl and imidazole in DMF giving the silyl ether (XIX). The cleavage of the cyclopropane ring of (XIX) with tert-butyl perbenzoate, followed by hydrolysis of the resulting ester yields the methanol derivative (XX), which is selectively reduced with Li in THF/NH3 affording the cis-isomer (XXI). Finally, this compound is oxidized with NaClO4 in tert-butanol, and desilylated with tetrabutylammonium fluoride to give the target oleanolic acid.
| 【1】 Corey, E.J.; Lee, J.; Enantioselective total synthesis of oleanolic acid, erythrodiol, beta-amyrin, and other pentacyclic triterpenes from a common intermediate. J Am Chem Soc 1993, 115, 8873. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 35735 | (3S)-3-[(3E,7E)-3,7-dimethyl-10-(2,7,7-trimethyl-3,4,5,6,7,8-hexahydro-1-naphthalenyl)-3,7-decadienyl]-2,2-dimethyloxirane | C29H46O | 详情 | 详情 | |
| (XV) | 35283 | (3S,4aR,6aR,6bS,14aR,14bR)-4,4,6a,6b,11,11,14b-heptamethyl-1,2,3,4,4a,5,6,6a,6b,7,8,9,10,11,12,14,14a,14b-octadecahydro-3-picenyl benzoate | C36H50O2 | 详情 | 详情 | |
| (XVI) | 35736 | (3S,4aR,6aR,6bS,14aR,14bR)-4,4,6a,6b,11,11,14b-heptamethyl-1,2,3,4,4a,5,6,6a,6b,7,8,10,11,12,13,14,14a,14b-octadecahydro-3-picenyl benzoate | C36H50O2 | 详情 | 详情 | |
| (XVII) | 35284 | C37H52O2 | 详情 | 详情 | ||
| (XVIII) | 35285 | C30H48O | 详情 | 详情 | ||
| (XIX) | 35286 | C36H62OSi | 详情 | 详情 | ||
| (XX) | 35287 | [(6aS,6bR,8aR,10S,12aR,12bR)-10-[[tert-butyl(dimethyl)silyl]oxy]-2,2,6a,6b,9,9,12a-heptamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b-hexadecahydro-4(2H)-picenyl]methanol | C36H62O2Si | 详情 | 详情 | |
| (XXI) | 35288 | [(6aS,6bR,8aR,10S,12aR,12bR,14bS)-10-[[tert-butyl(dimethyl)silyl]oxy]-2,2,6a,6b,9,9,12a-heptamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydro-4(2H)-picenyl]methanol | C36H64O2Si | 详情 | 详情 |