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【结 构 式】 
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【分子编号】46159 【品名】(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-10,13-cyclohexadecadiene-2,6-dione 【CA登记号】 |
【 分 子 式 】C39H67NO5SSi2 【 分 子 量 】718.20172 【元素组成】C 65.22% H 9.4% N 1.95% O 11.14% S 4.46% Si 7.82% |
合成路线1
该中间体在本合成路线中的序号：(XXIX)The macrolactonization of (XXVIII) by means of 2,4,6-trichlorobenzoyl chloride and TEA in THF provides the protected macrolactone (XXIX), which is deprotected with TFA in dichloromethane to give the trienic macrolactone (XXX). Selective hydrogenation of the disubstituted double bond of (XXX) by means of potassium azodicarboxylate (DKAD) and AcOH in dichloromethane yields the precursor (XXXI), which is finally epoxidized with dimethyldioxirane (XXXII) in dichloromethane to afford the target epothilone B.
| 【1】 White, J.D.; Carter, R.G.; Sundermann, K.F.; Wartmann, M.; Total synthesis of epothilone B, epothilone D, and cis- and trans-9,10-dehydroepothilone D. J Am Chem Soc 2001, 123, 23, 5407. |
| 【2】 White, J.D.; et al.; A highly stereoselective synthesis of epothilone B. J Org Chem 1999, 64, 3, 684. |
| 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) | 46158 | (3S,6R,7S,8S,9Z,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-9,12,16-heptadecatrienoic acid | C39H69NO6SSi2 | 详情 | 详情 | |
| (XXIX) | 46159 | (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-10,13-cyclohexadecadiene-2,6-dione | C39H67NO5SSi2 | 详情 | 详情 | |
| (XXX) | 46160 | (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-10,13-cyclohexadecadiene-2,6-dione | C27H39NO5S | 详情 | 详情 | |
| (XXXI) | 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 | |
| (XXXII) | 31501 | 3,3-dimethyl-1,2-dioxirane | C3H6O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)The reaction of chiral aldehyde (I) with dimethyl diazomethylphosphonate (II) by means of tBu-OK in THF gives the acetylenic ester (III), which is condensed with ally bromide derivative (IV) by means of CuI and TEA in DMF/ethyl ether to yield the dienyne (V). The partial hydrogenation of (V) over a Lindlar catalyst in hexane affords the trienoic ester (VI). The hydrolysis of (VI) with NaOH in warm isopropanol provides the corresponding carboxylic acid (VII), which is selectively desilylated with TBAF in THF to give the hydroxyacid (VIII). The macrolactonization of (VIII) by means of 2,4,6-trichlorobenzoyl chloride and TEA in benzene/THF yields the protected macrolactone (IX), which is deprotected with TFA in dichloromethane to afford the trienic macrolactone (X). Selective hydrogenation of the disubstituted double bond of (X) by means of potassium azodicarboxylate (DKAD) and HOAc in dichloromethane provides the precursor (XI), which is finally epoxidated with dimethyldioxirane (XII) in dichloromethane to furnish the target epothilone B.
| 【1】 White, J.D.; et al.; Improved synthesis of epothilone B employing alkylation of an alkyne for assembly of subunits. Org Lett 1999, 1, 9, 1431. |
| 【2】 White, J.D.; et al.; A highly stereoselective synthesis of epothilone B. J Org Chem 1999, 64, 3, 684. |
| 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) | 46155 | methyl (3S,6R,7S,8R)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5,9-dioxononanoate | C26H52O6Si2 | 详情 | 详情 | |
| (II) | 42709 | Diazomethylphoshonic acid dimethyl ester | 27491-70-9 | C3H7N2O3P | 详情 | 详情 |
| (III) | 46161 | methyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-9-decynoate | C27H52O5Si2 | 详情 | 详情 | |
| (IV) | 46147 | 4-((1E,3S,5Z)-7-bromo-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-1,5-heptadienyl)-2-methyl-1,3-thiazole; (1S,3Z)-5-bromo-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl tert-butyl(dimethyl)silyl ether | C19H32BrNOSSi | 详情 | 详情 | |
| (V) | 46162 | methyl (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadien-9-ynoate | C46H83NO6SSi3 | 详情 | 详情 | |
| (VI) | 46156 | methyl (3S,6R,7S,8S,9Z,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-9,12,16-heptadecatrienoate | C46H85NO6SSi3 | 详情 | 详情 | |
| (VII) | 46157 | (3S,6R,7S,8S,9Z,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-9,12,16-heptadecatrienoic acid | C45H83NO6SSi3 | 详情 | 详情 | |
| (VIII) | 46158 | (3S,6R,7S,8S,9Z,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-9,12,16-heptadecatrienoic acid | C39H69NO6SSi2 | 详情 | 详情 | |
| (IX) | 46159 | (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-10,13-cyclohexadecadiene-2,6-dione | C39H67NO5SSi2 | 详情 | 详情 | |
| (X) | 46160 | (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-10,13-cyclohexadecadiene-2,6-dione | C27H39NO5S | 详情 | 详情 | |
| (XI) | 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 | |
| (XII) | 31501 | 3,3-dimethyl-1,2-dioxirane | C3H6O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XLII)The oxidation of (XXXVIII) with TPAP and NMO in acetonitrile gives the carbaldehyde (XXXIX), which is condensed with the intermediate phosphonium bromide (XVII) by means of LiHMDS in THF to yield the heptadecadienoic ester (XL). The regioselective deprotection of (XL) by means of Tms-OTf in dichloromethane affords the hydroxyacid (XLI), which is submitted to a macrocyclization by means of 2,4,6-trichlorobenzoyl chloride and TEA in THF to provide the protected didehydro precursor (XLII). The desilylation of (XLII) by means of TFA in dichloromethane yields the free didehydro precursor (XLIII), which is hydrogenated by means of 2,4,6-tri-isopropylbenzenesulfonyl hydrazide and TEA in refluxing ethyl ether to afford epothilone D (XLIII). Finally, this compound is epoxidated by means of dimethyldioxirane (DMDO) in dichloromethane.
| 【1】 Potier, P.; Ermolenko, M.S.; Synthesis of epothilones B and D from D-glucose. Tetrahedron Lett 2002, 43, 16, 2895. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVII) | 46148 | [(3Z,6S,7E)-6-[[tert-butyl(dimethyl)silyl]oxy]-3,7-dimethyl-8-(2-methyl-1,3-thiazol-4-yl)-3,7-octadienyl](triphenyl)phosphonium bromide | C38H49BrNOPSSi | 详情 | 详情 | |
| (XXXVIII) | 54362 | tert-butyl (3S,6R,7S,8S)-3,7-bis{[tert-butyl(dimethyl)silyl]oxy}-9-hydroxy-4,4,6,8-tetramethyl-5-oxononanoate | C29H60O6Si2 | 详情 | 详情 | |
| (XXXIX) | 54363 | tert-butyl (3S,6R,7S,8R)-3,7-bis{[tert-butyl(dimethyl)silyl]oxy}-4,4,6,8-tetramethyl-5,9-dioxononanoate | C29H58O6Si2 | 详情 | 详情 | |
| (XL) | 54364 | tert-butyl (3S,6R,7S,8S,9Z,12Z,15S,16E)-3,7,15-tris{[tert-butyl(dimethyl)silyl]oxy}-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-9,12,16-heptadecatrienoate | C49H91NO6SSi3 | 详情 | 详情 | |
| (XLI) | 46158 | (3S,6R,7S,8S,9Z,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-9,12,16-heptadecatrienoic acid | C39H69NO6SSi2 | 详情 | 详情 | |
| (XLII) | 46159 | (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-10,13-cyclohexadecadiene-2,6-dione | C39H67NO5SSi2 | 详情 | 详情 | |
| (XLIII) | 46160 | (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-10,13-cyclohexadecadiene-2,6-dione | C27H39NO5S | 详情 | 详情 | |
| (XLIV) | 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4
该中间体在本合成路线中的序号：(XXIX)The macrolactonization of (XXVIII) by means of 2,4,6-trichlorobenzoyl chloride and TEA in THF provides the protected macrolactone (XXIX), which is deprotected with TFA in dichloromethane to give the trienic macrolactone (XXX). Finally, the selective hydrogenation of the disubstituted double bond of (XXX) by means of potassium azodicarboxylate (DKAD) and HOAc in dichloromethane yields the target epothilone D.
| 【1】 White, J.D.; Carter, R.G.; Sundermann, K.F.; Wartmann, M.; Total synthesis of epothilone B, epothilone D, and cis- and trans-9,10-dehydroepothilone D. J Am Chem Soc 2001, 123, 23, 5407. |
| 【2】 White, J.D.; et al.; A highly stereoselective synthesis of epothilone B. J Org Chem 1999, 64, 3, 684. |
| 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) | 46158 | (3S,6R,7S,8S,9Z,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-9,12,16-heptadecatrienoic acid | C39H69NO6SSi2 | 详情 | 详情 | |
| (XXIX) | 46159 | (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-10,13-cyclohexadecadiene-2,6-dione | C39H67NO5SSi2 | 详情 | 详情 | |
| (XXX) | 46160 | (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-10,13-cyclohexadecadiene-2,6-dione | C27H39NO5S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IX)The reaction of chiral aldehyde (I) with dimethyl diazomethylphosphonate (II) by means of tBu-OK in THF gives the acetylenic ester (III), which is condensed with ally bromide derivative (IV) by means of CuI and TEA in DMF/ethyl ether to yield the dienyne (V). The partial hydrogenation of (V) over a Lindlar catalyst in hexane affords the trienoic ester (VI). The hydrolysis of (VI) with NaOH in warm isopropanol provides the corresponding carboxylic acid (VII), which is selectively desilylated with TBAF in THF to give the hydroxyacid (VIII). The macrolactonization of (VIII) by means of 2,4,6-trichlorobenzoyl chloride and TEA in benzene/THF yields the protected macrolactone (IX), which is deprotected with TFA in dichloromethane to afford the trienic macrolactone (X) (1). Finally, the selective hydrogenation of the disubstituted double bond of (X) by means of potassium azodicarboxylate (DKAD) and HOAc in dichloromethane provides the target epothilone D.
| 【1】 White, J.D.; et al.; A highly stereoselective synthesis of epothilone B. J Org Chem 1999, 64, 3, 684. |
| 【2】 White, J.D.; et al.; Improved synthesis of epothilone B employing alkylation of an alkyne for assembly of subunits. Org Lett 1999, 1, 9, 1431. |
| 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) | 46155 | methyl (3S,6R,7S,8R)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5,9-dioxononanoate | C26H52O6Si2 | 详情 | 详情 | |
| (II) | 42709 | Diazomethylphoshonic acid dimethyl ester | 27491-70-9 | C3H7N2O3P | 详情 | 详情 |
| (III) | 46161 | methyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-9-decynoate | C27H52O5Si2 | 详情 | 详情 | |
| (IV) | 46147 | 4-((1E,3S,5Z)-7-bromo-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-1,5-heptadienyl)-2-methyl-1,3-thiazole; (1S,3Z)-5-bromo-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl tert-butyl(dimethyl)silyl ether | C19H32BrNOSSi | 详情 | 详情 | |
| (V) | 46162 | methyl (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadien-9-ynoate | C46H83NO6SSi3 | 详情 | 详情 | |
| (VI) | 46156 | methyl (3S,6R,7S,8S,9Z,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-9,12,16-heptadecatrienoate | C46H85NO6SSi3 | 详情 | 详情 | |
| (VII) | 46157 | (3S,6R,7S,8S,9Z,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-9,12,16-heptadecatrienoic acid | C45H83NO6SSi3 | 详情 | 详情 | |
| (VIII) | 46158 | (3S,6R,7S,8S,9Z,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-9,12,16-heptadecatrienoic acid | C39H69NO6SSi2 | 详情 | 详情 | |
| (IX) | 46159 | (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-10,13-cyclohexadecadiene-2,6-dione | C39H67NO5SSi2 | 详情 | 详情 | |
| (X) | 46160 | (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-10,13-cyclohexadecadiene-2,6-dione | C27H39NO5S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XLII)The oxidation of (XXXVIII) with TPAP and NMO in acetonitrile gives the carbaldehyde (XXXIX), which is condensed with the intermediate phosphonium bromide (XVII) by means of LiHMDS in THF to yield the heptadecadienoic ester (XL). The regioselective deprotection of (XL) by means of Tms-OTf in dichloromethane affords the hydroxyacid (XLI), which is submitted to a macrocyclization by means of 2,4,6-trichlorobenzoyl chloride and TEA in THF to provide the protected didehydro precursor (XLII). The desilylation of (XLII) by means of TFA in dichloromethane yields the free didehydro precursor (XLIII), which is finally hydrogenated by means of 2,4,6-tri-isopropylbenzenesulfonyl hydrazide and TEA in refluxing ethyl ether to afford the target epothilone D.
| 【1】 Potier, P.; Ermolenko, M.S.; Synthesis of epothilones B and D from D-glucose. Tetrahedron Lett 2002, 43, 16, 2895. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVII) | 46148 | [(3Z,6S,7E)-6-[[tert-butyl(dimethyl)silyl]oxy]-3,7-dimethyl-8-(2-methyl-1,3-thiazol-4-yl)-3,7-octadienyl](triphenyl)phosphonium bromide | C38H49BrNOPSSi | 详情 | 详情 | |
| (XXXVIII) | 54362 | tert-butyl (3S,6R,7S,8S)-3,7-bis{[tert-butyl(dimethyl)silyl]oxy}-9-hydroxy-4,4,6,8-tetramethyl-5-oxononanoate | C29H60O6Si2 | 详情 | 详情 | |
| (XXXIX) | 54363 | tert-butyl (3S,6R,7S,8R)-3,7-bis{[tert-butyl(dimethyl)silyl]oxy}-4,4,6,8-tetramethyl-5,9-dioxononanoate | C29H58O6Si2 | 详情 | 详情 | |
| (XL) | 54364 | tert-butyl (3S,6R,7S,8S,9Z,12Z,15S,16E)-3,7,15-tris{[tert-butyl(dimethyl)silyl]oxy}-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-9,12,16-heptadecatrienoate | C49H91NO6SSi3 | 详情 | 详情 | |
| (XLI) | 46158 | (3S,6R,7S,8S,9Z,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-9,12,16-heptadecatrienoic acid | C39H69NO6SSi2 | 详情 | 详情 | |
| (XLII) | 46159 | (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-10,13-cyclohexadecadiene-2,6-dione | C39H67NO5SSi2 | 详情 | 详情 | |
| (XLIII) | 46160 | (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-10,13-cyclohexadecadiene-2,6-dione | C27H39NO5S | 详情 | 详情 |