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【结 构 式】 
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【分子编号】46132 【品名】(4S,6R,7S,8S,9S,16S)-8-[[tert-butyl(dimethyl)silyl]oxy]-4,6-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecen-2-one 【CA登记号】 |
【 分 子 式 】C33H57NO5SSi 【 分 子 量 】607.97082 【元素组成】C 65.19% H 9.45% N 2.3% O 13.16% S 5.27% Si 4.62% |
合成路线1
该中间体在本合成路线中的序号：(XXXIII)Hydrolysis of the dimethylacetal group of (XXVIII) with Ts-OH in dioxane/water yields the corresponding aldehyde (XXIX), which is submitted to an intramolecular aldolization by means of KHMDS in THF to afford a mixture of diastereomeric macrolactones (XXX) and (XXXI). The undesired isomer (XXX) was recovered, oxidized with DMP to the ketone (XXXII) and reduced again with NaBH4 to provide high yields of the desired isomer (XXXI). Selective desilylation of (XXXI) with HF/pyridine in THF gives the diol (XXXIII), which is selectively monosilylated with Tbdms-OTf and lutidine in dichloromethane, yielding the bis-silylated triol (XXXIV). The oxidation of the free OH group of (XXXIV) with DMP in dichloromethane affords the corresponding ketonic derivative (XXXV), which is deprotected with HF/pyridine in THF, providing the free dihydroxy compound (XXXVI). Finally, this compound is epoxidized by means of dimethyldioxirane (DMDO) in dichloromethane to afford the target epothilone B.
| 【1】 Meng, D.; et al.; Total syntheses of epothilones A and B. J Am Chem Soc 1997, 119, 42, 10073. |
| 【2】 Bertinato, P.; Danishefsky, S.J.; Su, D.-S.; Kamenecka, T.; Meng, D.F.; Sorensen, E.J.; Savin, K.A.; Chou, T.-C.; Balog, A. (Sloan-Kettering Institute); Synthesis of epothilones, intermediates thereto, analogues and uses thereof. JP 2001507716; US 6242469; WO 9901124 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXVIII) | 46127 | (1S,3Z,8S,9S,10R,11R)-9-[[tert-butyl(dimethyl)silyl]oxy]-13,13-dimethoxy-4,8,10,12,12-pentamethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-11-[(triphenylsilyl)oxy]-3-tridecenyl acetate | C53H77NO6SSi2 | 详情 | 详情 | |
| (XXIX) | 46128 | (1S,3Z,8S,9S,10R,11R)-9-[[tert-butyl(dimethyl)silyl]oxy]-4,8,10,12,12-pentamethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-13-oxo-11-[(triphenylsilyl)oxy]-3-tridecenyl acetate | C51H71NO5SSi2 | 详情 | 详情 | |
| (XXX) | 46129 | (4R,6R,7R,8S,9S,16S)-8-[[tert-butyl(dimethyl)silyl]oxy]-4-hydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-6-[(triphenylsilyl)oxy]oxa-13-cyclohexadecen-2-one | C51H71NO5SSi2 | 详情 | 详情 | |
| (XXXI) | 46130 | (4S,6R,7R,8S,9S,16S)-8-[[tert-butyl(dimethyl)silyl]oxy]-4-hydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-6-[(triphenylsilyl)oxy]oxa-13-cyclohexadecen-2-one | C51H71NO5SSi2 | 详情 | 详情 | |
| (XXXII) | 46131 | (6R,7R,8S,9S,16S)-8-[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-6-[(triphenylsilyl)oxy]oxa-13-cyclohexadecene-2,4-dione | C51H69NO5SSi2 | 详情 | 详情 | |
| (XXXIII) | 46132 | (4S,6R,7S,8S,9S,16S)-8-[[tert-butyl(dimethyl)silyl]oxy]-4,6-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecen-2-one | C33H57NO5SSi | 详情 | 详情 | |
| (XXXIV) | 46133 | (4S,6R,7S,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-6-hydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecen-2-one | C39H71NO5SSi2 | 详情 | 详情 | |
| (XXXV) | 40836 | (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C39H69NO5SSi2 | 详情 | 详情 | |
| (XXXVI) | 40837 | (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C27H41NO5S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXXIII)Hydrolysis of the dimethylacetal group of (XXVIII) with Ts-OH in dioxane/water yields the corresponding aldehyde (XXIX), which is submitted to a intramolecular aldolization by means of KHMDS in THF to afford a mixture of diastereomeric macrolactones (XXX) and (XXXI). The undesired isomer (XXX) was recovered, oxidized with DMP to the ketone (XXXII) and reduced again with NaBH4 to provide high yields of the desired isomer (XXXI). Selective desilylation of (XXXI) with HF/pyridine in THF gives de diol (XXXIII), which is selectively monosilylated with Tbdms-OTf and lutidine in dichloromethane, yielding the bis-silylated triol (XXXIV). The oxidation of the free OH group of (XXXIV) with DMP in dichloromethane affords the corresponding ketonic derivative (XXXV), which is finally deprotected with HF/pyridine in THF, providing the target epothilone D.
| 【1】 Meng, D.; et al.; Total syntheses of epothilones A and B. J Am Chem Soc 1997, 119, 42, 10073. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXVIII) | 46127 | (1S,3Z,8S,9S,10R,11R)-9-[[tert-butyl(dimethyl)silyl]oxy]-13,13-dimethoxy-4,8,10,12,12-pentamethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-11-[(triphenylsilyl)oxy]-3-tridecenyl acetate | C53H77NO6SSi2 | 详情 | 详情 | |
| (XXIX) | 46128 | (1S,3Z,8S,9S,10R,11R)-9-[[tert-butyl(dimethyl)silyl]oxy]-4,8,10,12,12-pentamethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-13-oxo-11-[(triphenylsilyl)oxy]-3-tridecenyl acetate | C51H71NO5SSi2 | 详情 | 详情 | |
| (XXX) | 46129 | (4R,6R,7R,8S,9S,16S)-8-[[tert-butyl(dimethyl)silyl]oxy]-4-hydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-6-[(triphenylsilyl)oxy]oxa-13-cyclohexadecen-2-one | C51H71NO5SSi2 | 详情 | 详情 | |
| (XXXI) | 46130 | (4S,6R,7R,8S,9S,16S)-8-[[tert-butyl(dimethyl)silyl]oxy]-4-hydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-6-[(triphenylsilyl)oxy]oxa-13-cyclohexadecen-2-one | C51H71NO5SSi2 | 详情 | 详情 | |
| (XXXII) | 46131 | (6R,7R,8S,9S,16S)-8-[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-6-[(triphenylsilyl)oxy]oxa-13-cyclohexadecene-2,4-dione | C51H69NO5SSi2 | 详情 | 详情 | |
| (XXXIII) | 46132 | (4S,6R,7S,8S,9S,16S)-8-[[tert-butyl(dimethyl)silyl]oxy]-4,6-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecen-2-one | C33H57NO5SSi | 详情 | 详情 | |
| (XXXIV) | 46133 | (4S,6R,7S,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-6-hydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecen-2-one | C39H71NO5SSi2 | 详情 | 详情 | |
| (XXXV) | 40836 | (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C39H69NO5SSi2 | 详情 | 详情 |