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【结 构 式】 
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【分子编号】52584 【品名】3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-15-[({[2-(trimethyl-lambda~4~-sulfanyl)ethyl]oxy}methyl)oxy]-12,16-heptadecadienoic acid 【CA登记号】 |
【 分 子 式 】C39H71NO7S2Si 【 分 子 量 】758.21278 【元素组成】C 61.78% H 9.44% N 1.85% O 14.77% S 8.46% Si 3.7% |
合成路线1
该中间体在本合成路线中的序号：(XVIIIa)The reaction of bromide (V) with Mg and then with CuBr and propyne gives a cuprate complex that is treated with 1-hexyne, yielding the nonisolated copper complex (VII). The reaction of the protected chiral epoxide (IX) (obtained by reaction of the epoxide (VIII) with Pmb-Br, NaH and TBAI in THF) with copper complex (VII) affords the (Z)-alkene (X), which is treated with Sem-Cl and DIEA to protect its OH group, providing (XI). Selective elimination of the Pmb protecting group of (XI) with DDQ furnishes the secondary alcohol (XII), which is oxidized under Swern protocol to the ketone (XIII) with (COCl)2 and TEA in dichloromethane. The Wadsworth-Emmons olefination of (XIII) with the known phosphonate (XIV) by means of BuLi in THF gives pure triene (XV), which is submitted to a diastereoselective hydroboration with bis(diisopinocampheyl)borane and oxidative workup to yield the primary alcohol (XVI). The Swern oxidation of (XVI) with (COCl)2 affords the aldehyde (XVII), which is submitted to an aldol condensation with the intermediate oxoacid (V) by means of LDA in THF to provide the aldol product (XVIII) as a (6R,7S)(6S,7R) diastereomeric mixture.
| 【1】 Valluri, M.; et al.; Total synthesis of epothilone B. Org Lett 2001, 3, 23, 3607. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVIIIa) | 52584 | 3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-15-[({[2-(trimethyl-lambda~4~-sulfanyl)ethyl]oxy}methyl)oxy]-12,16-heptadecadienoic acid | C39H71NO7S2Si | 详情 | 详情 | |
| (XVIIIb) | 52585 | 3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-15-[({[2-(trimethyl-lambda~4~-sulfanyl)ethyl]oxy}methyl)oxy]-12,16-heptadecadienoic acid | C39H71NO7S2Si | 详情 | 详情 | |
| (V) | 43166 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid | C15H30O4Si | 详情 | 详情 | |
| (VI) | 52575 | 5-bromo-2-methyl-1-pentene | C6H11Br | 详情 | 详情 | |
| (VII) | 52576 | (2,6-dimethyl-1,6-heptadienyl)(1-hexynyl)copper | C15H24Cu | 详情 | 详情 | |
| (VIII) | 52577 | 1-(2-oxiranyl)-1-ethanol | n/a | C4H8O2 | 详情 | 详情 |
| (IX) | 52578 | methyl 4-({[1-(2-oxiranyl)ethyl]oxy}methyl)phenyl ether; 2-[1-({[4-(methyloxy)phenyl]methyl}oxy)ethyl]oxirane | C2H5NS | 详情 | 详情 | |
| (X) | 52579 | 6,10-dimethyl-2-({[4-(methyloxy)phenyl]methyl}oxy)-5,10-undecadien-3-ol | C21H32O3 | 详情 | 详情 | |
| (XI) | 52580 | 4-(3,7-dimethyl-2,7-octadienyl)-3,10,10-trimethyl-1-[4-(methyloxy)phenyl]-2,5,7-trioxa-10lambda~4~-thiaundecane; 4,8-dimethyl-1-[1-({[4-(methyloxy)phenyl]methyl}oxy)ethyl]-3,8-nonadienyl {[2-(trimethyl-lambda~4~-sulfanyl)ethyl]oxy}methyl ether | C27H46O4S | 详情 | 详情 | |
| (XII) | 52581 | 6,10-dimethyl-3-[({[2-(trimethyl-lambda~4~-sulfanyl)ethyl]oxy}methyl)oxy]-5,10-undecadien-2-ol | C19H38O3S | 详情 | 详情 | |
| (XIII) | 52582 | 6,10-dimethyl-3-[({[2-(trimethyl-lambda~4~-sulfanyl)ethyl]oxy}methyl)oxy]-5,10-undecadien-2-one | C19H36O3S | 详情 | 详情 | |
| (XIV) | 44442 | diethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate | C9H16NO3PS | 详情 | 详情 | |
| (XV) | 52583 | 4,8-dimethyl-1-[1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3,8-nonadienyl {[2-(trimethyl-lambda~4~-sulfanyl)ethyl]oxy}methyl ether; 2-methyl-4-{2,6,10-trimethyl-3-[({[2-(trimethyl-lambda~4~-sulfanyl)ethyl]oxy}methyl)oxy]-1,5,10-undecatrienyl}-1,3-thiazole | C24H41NO2S2 | 详情 | 详情 | |
| (XVI) | 51454 | (2S,6Z,9S,10E)-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-9-[[2-(trimethyl-lambda(4)-sulfanyl)ethoxy]methoxy]-6,10-undecadien-1-ol | C24H43NO3S2 | 详情 | 详情 | |
| (XVII) | 51455 | (2S,6Z,9S,10E)-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-9-[[2-(trimethyl-lambda(4)-sulfanyl)ethoxy]methoxy]-6,10-undecadienal | C24H41NO3S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVIIIa)The treatment of (XVIII) with Troc-Cl and pyridine gives fully protected (XIX) as the same diastereomeric mixture, which is selectively deprotected at the Sem group with TFA in dichloromethane to yield the corresponding mixture of hydroxyacids (XX). The macrolactonization of (XX) by the Yamaguchi method (2,4,6-trichlrobenzoyl chloride, TEA and DMAP in toluene) gives the diastereomeric mixture of lactones (XXI), which are readily separated by flash column chromatography. The desired diastereomer (XXII) is desilylated with HF and pyridine, yielding the hydroxylactone (XXIII), which is treated with Zn and NH4Cl in refluxing aqueous methanol to eliminate the Troc protecting group and provide the unprotected precursor (XXIV). Finally, this compound is epoxidated with methyl(trifluoromethyl)dioxirane (MTFDO) to afford the target epothilone B.
| 【1】 Valluri, M.; et al.; Total synthesis of epothilone B. Org Lett 2001, 3, 23, 3607. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVIIIa) | 52584 | 3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-15-[({[2-(trimethyl-lambda~4~-sulfanyl)ethyl]oxy}methyl)oxy]-12,16-heptadecadienoic acid | C39H71NO7S2Si | 详情 | 详情 | |
| (XVIIIb) | 52585 | 3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-15-[({[2-(trimethyl-lambda~4~-sulfanyl)ethyl]oxy}methyl)oxy]-12,16-heptadecadienoic acid | C39H71NO7S2Si | 详情 | 详情 | |
| (XIXa) | 52586 | 3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-7-({[(2,2,2-trichloroethyl)oxy]carbonyl}oxy)-15-[({[2-(trimethyl-lambda~4~-sulfanyl)ethyl]oxy}methyl)oxy]-12,16-heptadecadienoic acid | C42H72Cl3NO9S2Si | 详情 | 详情 | |
| (XIXb) | 52587 | 3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-7-({[(2,2,2-trichloroethyl)oxy]carbonyl}oxy)-15-[({[2-(trimethyl-lambda~4~-sulfanyl)ethyl]oxy}methyl)oxy]-12,16-heptadecadienoic acid | C42H72Cl3NO9S2Si | 详情 | 详情 | |
| (XXa) | 52588 | 3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-7-({[(2,2,2-trichloroethyl)oxy]carbonyl}oxy)-12,16-heptadecadienoic acid | C36H58Cl3NO8SSi | 详情 | 详情 | |
| (XXb) | 52589 | 3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-7-({[(2,2,2-trichloroethyl)oxy]carbonyl}oxy)-12,16-heptadecadienoic acid | C36H58Cl3NO8SSi | 详情 | 详情 | |
| (XXIa),(XXII) | 52590 | 4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-2,6-dioxooxa-13-cyclohexadecen-8-yl 2,2,2-trichloroethyl carbonate | C36H56Cl3NO7SSi | 详情 | 详情 | |
| (XXIb) | 52591 | 4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-2,6-dioxooxa-13-cyclohexadecen-8-yl 2,2,2-trichloroethyl carbonate | C36H56Cl3NO7SSi | 详情 | 详情 | |
| (XXIII) | 52592 | 4-hydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-2,6-dioxooxa-13-cyclohexadecen-8-yl 2,2,2-trichloroethyl carbonate | C30H42Cl3NO7S | 详情 | 详情 | |
| (XXIV) | 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 |