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【结 构 式】 
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【分子编号】44473 【品名】(3S,6R,7S,8S,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid 【CA登记号】 |
【 分 子 式 】C38H69NO6SSi2 【 分 子 量 】724.206 【元素组成】C 63.02% H 9.6% N 1.93% O 13.26% S 4.43% Si 7.76% |
合成路线1
该中间体在本合成路线中的序号：(XXXI)Intermediate (XXVIII) separated at the carboxylic acid (XXX) step. The full silylation of (XXVIII) with Tbdms-OTf and lutidine in dichloromethane gives the tetrasilyloxy compound (XXIX), which is stepwise desilylated first with K2CO3 in methanol to yield the carboxylic acid (XXX), and then with TBAF in THF to afford the hydroxyacid (XXXI). The macrolactonization of (XXXI) was carried out with the Yamaguchi method using 2,4,6-trichlorobenzoyl chloride, TEA and DMAP in THF to yield the silylated macrolactone (XXXII), which is deprotected with TFA in dichloromethane to afford the dihydroxymacrolactone (XXXIII). Finally, the double bond of (XXXIII) is epoxidated with methyl(trifluoromethyl)dioxirane (A) in acetonitrile.
| 【1】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 43177 | 3-methyl-3-(trifluoromethyl)-1,2-dioxirane | C3H3F3O2 | 详情 | 详情 | |
| (XXVIII) | 44470 | (3S,6R,7S,8S,12Z,15S,16E)-3,15-bis[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid | C38H69NO6SSi2 | 详情 | 详情 | |
| (XXIX) | 44471 | tert-butyl(dimethyl)silyl (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate | C50H97NO6SSi4 | 详情 | 详情 | |
| (XXX) | 44472 | (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid | C44H83NO6SSi3 | 详情 | 详情 | |
| (XXXI) | 44473 | (3S,6R,7S,8S,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid | C38H69NO6SSi2 | 详情 | 详情 | |
| (XXXII) | 44446 | (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C38H67NO5SSi2 | 详情 | 详情 | |
| (XXXIII) | 44467 | 4-((1E,3S,5Z,10S)-3,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,10-dimethyl-1,5-undecadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienyl ether | C29H55NO2SSi2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXXVI)Assembly of the target compound: The condensation of intermediates (XXI) and (XXXIV) by means of 9-BBN, a PdCl2 catalyst and K3PO4 in hot DMF/water gives the adduct (XXXV), which is hydrolyzed with NaOH in methanol/water to yield the hydroxyacid (XXXVI). The macrolactonization of (XXXVI) by the Yamaguchi procedure using 2,4,6-trichlorobenzoyl chloride, TEA and DMAP in THF affords the macrolactone (XXXVII), which is desilylated with HF and pyridine in THF, furnishing the dihydroxylactone (XXXVIII). Finally, this compound is epoxidated by means of dimethyldioxirane (XXXIX) in dichloromethane.
| 【1】 Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXI) | 44519 | phenyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-10-undecenoate | C33H58O5Si2 | 详情 | 详情 | |
| (XXXIV) | 44493 | (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate | C13H16INO2S | 详情 | 详情 | |
| (XXXV) | 44528 | phenyl (3S,6R,7S,8S,12Z,15S,16E)-15-(acetoxy)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate | C46H75NO7SSi2 | 详情 | 详情 | |
| (XXXVI) | 44473 | (3S,6R,7S,8S,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid | C38H69NO6SSi2 | 详情 | 详情 | |
| (XXXVII) | 44446 | (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C38H67NO5SSi2 | 详情 | 详情 | |
| (XXXVIII) | 44447 | (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C26H39NO5S | 详情 | 详情 | |
| (XXXIX) | 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：(XLV)Alternatively, the hydrolysis of the intermediate dimethylacetal (XXVII) with TsOH in dioxane/water gives the aldehyde (XXXVII), which is condensed with tert-butyl acetate (XXXVIII) by means of LDA in THF, yielding the hydroxyester (XXXIX). The desilylation of (XXXIX) with HF/pyridine in THF affords the trihydroxy compound (XL), which is selectively resilylated with Tbdms-OTf and lutidine, providing the bis-silylated compound (XLI). The oxidation of the free OH group of (XLI) with DMP in dichloromethane gives the ketonic compound (XLII), which is treated with Tbdms-OTf and lutidine in dichloromethane to furnish the silyl ester (XLIII). The condensation of (XLIII) with the thiazole intermediate (IX) as before gives the adduct (XLIV), which is hydrolyzed by means of K2CO3 in methanol/water, yielding the hydroxyacid (XLV). The intramolecular lactonization of (XLV) by means of 2,4,6-trichlorobenzoyl chloride, TEA and DMAP in toluene affords the previously reported macrolactone (XXXV), which is desilylated with HF/pyridine to (XXXVI) and finally epoxidated with DMDO in dichloromethane.
| 【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 |
|---|---|---|---|---|---|---|
| (IX) | 44493 | (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate | C13H16INO2S | 详情 | 详情 | |
| (XXVII) | 44549 | tert-butyl(dimethyl)silyl (1S,2S)-1-[(1R,2R)-4,4-dimethoxy-1,3,3-trimethyl-2-[(triphenylsilyl)oxy]butyl]-2-methyl-4-pentenyl ether; (3R,4R,5S)-3-(2,2-dimethoxy-1,1-dimethylethyl)-4,7,7,8,8-pentamethyl-5-[(1S)-1-methyl-3-butenyl]-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane | C39H58O4Si2 | 详情 | 详情 | |
| (XXXV) | 44446 | (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C38H67NO5SSi2 | 详情 | 详情 | |
| (XXXVI) | 44447 | (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C26H39NO5S | 详情 | 详情 | |
| (XXXVII) | 44557 | (3R,4R,5S,6S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,2,4,6-tetramethyl-3-[(triphenylsilyl)oxy]-8-nonenal | C37H52O3Si2 | 详情 | 详情 | |
| (XXXVIII) | 15397 | tert-butyl acetate | 540-88-5 | C6H12O2 | 详情 | 详情 |
| (XXXIX) | 44558 | tert-butyl (3S,5R,6R,7S,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxy-4,4,6,8-tetramethyl-5-[(triphenylsilyl)oxy]-10-undecenoate | C43H64O5Si2 | 详情 | 详情 | |
| (XL) | 44559 | tert-butyl (3S,5R,6R,7S,8S)-3,5,7-trihydroxy-4,4,6,8-tetramethyl-10-undecenoate | C19H36O5 | 详情 | 详情 | |
| (XLI) | 44560 | tert-butyl (3S,5R,6S,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-4,4,6,8-tetramethyl-10-undecenoate | C31H64O5Si2 | 详情 | 详情 | |
| (XLII) | 44561 | tert-butyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-10-undecenoate | C31H62O5Si2 | 详情 | 详情 | |
| (XLIII) | 44562 | tert-butyl(dimethyl)silyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-10-undecenoate | C33H68O5Si3 | 详情 | 详情 | |
| (XLIV) | 44563 | tert-butyl(dimethyl)silyl (3S,6R,7S,8S,12Z,15S,16E)-15-(acetoxy)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate | C46H85NO7SSi3 | 详情 | 详情 | |
| (XLV) | 44473 | (3S,6R,7S,8S,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid | C38H69NO6SSi2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XXXI)Intermediate (XXVIII) separated at the carboxylic acid (XXX) step. The full silylation of (XVIII) with Tbdms-OTf and lutidine in dichloromethane gives the tetrasilyloxy compound (XXIX), which is stepwise desilylated first with K2CO3 in methanol to yield the carboxylic acid (XXX), and then with TBAF in THF to afford the hydroxyacid (XXXI). The macrolactonization of (XXXI) was carried out with the Yamaguchi method using 2,4,6-trichlorobenzoyl chloride, TEA and DMAP in THF to yield the silylated macrolactone (XXXII), which is deprotected with TFA in dichloromethane to afford the the target epothilone C.
| 【1】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974. |
| 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) | 44470 | (3S,6R,7S,8S,12Z,15S,16E)-3,15-bis[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid | C38H69NO6SSi2 | 详情 | 详情 | |
| (XXIX) | 44471 | tert-butyl(dimethyl)silyl (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate | C50H97NO6SSi4 | 详情 | 详情 | |
| (XXX) | 44472 | (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid | C44H83NO6SSi3 | 详情 | 详情 | |
| (XXXI) | 44473 | (3S,6R,7S,8S,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid | C38H69NO6SSi2 | 详情 | 详情 | |
| (XXXII) | 44446 | (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C38H67NO5SSi2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XXXVI)Assembly of the target compound: The condensation of intermediates (XXI) and (XXXIV) by means of 9-BBN, a PdCl2 catalyst and K3PO4 in hot DMF/water gives the adduct (XXXV), which is hydrolyzed with NaOH in methanol/water to yield the hydroxyacid (XXXVI). The macrolactonization of (XXXVI) by the Yamaguchi procedure using 2,4,6-trichlorobenzoyl chloride, TEA and DMAP in THF affords the macrolactone (XXXVII), which is finally desilylated with HF and pyridine in THF to provide the target epothilone C.
| 【1】 Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXI) | 44519 | phenyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-10-undecenoate | C33H58O5Si2 | 详情 | 详情 | |
| (XXXIV) | 44493 | (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate | C13H16INO2S | 详情 | 详情 | |
| (XXXV) | 44528 | phenyl (3S,6R,7S,8S,12Z,15S,16E)-15-(acetoxy)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate | C46H75NO7SSi2 | 详情 | 详情 | |
| (XXXVI) | 44473 | (3S,6R,7S,8S,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid | C38H69NO6SSi2 | 详情 | 详情 | |
| (XXXVII) | 44446 | (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C38H67NO5SSi2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XLV)Alternatively, the hydrolysis of the intermediate dimethylacetal (XXVII) with Ts-OH in dioxane/water gives the aldehyde (XXXVI), which is condensed with tert-butyl acetate (XXXVII) by means of LDA in THF, yielding the hydroxyester (XXXVIII). The desilylation of (XXXVIII) with HF/pyridine in THF affords the trihydroxy compound (XXXIX), which is selectively resilylated with Tbdms-OTf and lutidine, providing the bis-silylated compound (XL). The oxidation of the free OH group of (XL) with DMP in dichloromethane gives the ketonic compound (XLI), which is treated with Tbdms-OTf and lutidine in dichloromethane to furnish the silyl ester (XLII). The condensation of (XLII) with the thiazole intermediate (IX) as before gives the adduct (XLIII), which is hydrolyzed by means of K2CO3 in methanol/water, yielding the hydroxyacid (XLIV). The intramolecular lactonization of (XLIV) by means of 2,4,6-trichlorobenzoyl chloride, TEA and DMAP in toluene affords the already reported macrolactone (XXXV), which is finally desilylated with HF/pyridine to give the target epothilone C.
| 【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 |
|---|---|---|---|---|---|---|
| (IX) | 44493 | (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate | C13H16INO2S | 详情 | 详情 | |
| (XXVII) | 44549 | tert-butyl(dimethyl)silyl (1S,2S)-1-[(1R,2R)-4,4-dimethoxy-1,3,3-trimethyl-2-[(triphenylsilyl)oxy]butyl]-2-methyl-4-pentenyl ether; (3R,4R,5S)-3-(2,2-dimethoxy-1,1-dimethylethyl)-4,7,7,8,8-pentamethyl-5-[(1S)-1-methyl-3-butenyl]-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane | C39H58O4Si2 | 详情 | 详情 | |
| (XXXV) | 44446 | (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C38H67NO5SSi2 | 详情 | 详情 | |
| (XXXVII) | 44557 | (3R,4R,5S,6S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,2,4,6-tetramethyl-3-[(triphenylsilyl)oxy]-8-nonenal | C37H52O3Si2 | 详情 | 详情 | |
| (XXXVIII) | 15397 | tert-butyl acetate | 540-88-5 | C6H12O2 | 详情 | 详情 |
| (XXXIX) | 44558 | tert-butyl (3S,5R,6R,7S,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxy-4,4,6,8-tetramethyl-5-[(triphenylsilyl)oxy]-10-undecenoate | C43H64O5Si2 | 详情 | 详情 | |
| (XL) | 44559 | tert-butyl (3S,5R,6R,7S,8S)-3,5,7-trihydroxy-4,4,6,8-tetramethyl-10-undecenoate | C19H36O5 | 详情 | 详情 | |
| (XLI) | 44560 | tert-butyl (3S,5R,6S,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-4,4,6,8-tetramethyl-10-undecenoate | C31H64O5Si2 | 详情 | 详情 | |
| (XLII) | 44561 | tert-butyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-10-undecenoate | C31H62O5Si2 | 详情 | 详情 | |
| (XLIII) | 44562 | tert-butyl(dimethyl)silyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-10-undecenoate | C33H68O5Si3 | 详情 | 详情 | |
| (XLIV) | 44563 | tert-butyl(dimethyl)silyl (3S,6R,7S,8S,12Z,15S,16E)-15-(acetoxy)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate | C46H85NO7SSi3 | 详情 | 详情 | |
| (XLV) | 44473 | (3S,6R,7S,8S,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid | C38H69NO6SSi2 | 详情 | 详情 |