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【结 构 式】 
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【分子编号】52614 【品名】dimethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate 【CA登记号】 |
【 分 子 式 】C7H12NO3PS 【 分 子 量 】221.216982 【元素组成】C 38.01% H 5.47% N 6.33% O 21.7% P 14% S 14.5% |
合成路线1
该中间体在本合成路线中的序号：(XXIV)The macrolactonization of (XXII) under Yamaguchi conditions (2,4,6-trichlorobenzoyl chloride), followed by selective desilylation with H2SiF6, gives the macrolactone (XXII). The oxidation of the secondary OH group of (XXII) with (COCl)2 and TEA in DMSO/dichloromethane yields the ketone (XXIII), which is submitted to a Wadsworth-Emmons condensation with the phosphonate (XXIV) by means of BuLi in THF to afford the protected precursor (XXV). Elimination of the silyl protecting groups of (XXV) with TFA in dichloromethane affords the free precursor (XXVI), which is finally epoxidated with methyl(trifluoromethyl)dioxirane (MTFDO) in acetonitrile to afford the target epothilone A.
| 【1】 Hindupur, R.M.; et al.; Total synthesis of epothilone A. Tetrahedron Lett 2001, 42, 42, 7341. |
| 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) | 52612 | 3,7,16-tris{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-15-hydroxy-4,4,6,8-tetramethyl-5-oxo-12-heptadecenoic acid | C39H80O7Si3 | 详情 | 详情 | |
| (XXII) | 52611 | 4,8-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-16-(1-hydroxyethyl)-5,5,7,9-tetramethyloxa-13-cyclohexadecene-2,6-dione | C33H64O6Si2 | 详情 | 详情 | |
| (XXIII) | 52613 | 16-acetyl-4,8-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-5,5,7,9-tetramethyloxa-13-cyclohexadecene-2,6-dione | C33H62O6Si2 | 详情 | 详情 | |
| (XXIV) | 52614 | dimethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate | C7H12NO3PS | 详情 | 详情 | |
| (XXV) | 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 | |
| (XXVI) | 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 |
合成路线2
该中间体在本合成路线中的序号：(X)Synthesis of the target epothilone D. The condensation of 4-methyl-4-pentenyl bromide (XIII) with propyne (XIV) and 1-hexynyl lithium (XV) by means of CuBr in DMSO/ethyl ether gives the copper complex (XVI), which is condensed with the chiral epoxide (III) to yield the chiral unsaturated alcohol (XVII). The protection of the free OH group of (XVII) with Sem-Cl and DIEA in dichloromethane affords compound (XVIII). The selective cleavage of the Pmb-protecting group of (XVIII) by means of DDQ, followed by oxidation of the resulting alcohol with oxalyl chloride provides the methyl ketone (XIX), which is condensed with the intermediate phosphonate (X) by means of BuLi in THF to give the adduct (XX). The hydroxylation of the terminal vinylene double bond of (XX) by means of (Ipc)2BH and LiOH yields the primary alcohol (XXI), which is oxidized with (COCl)2, PTAP or DMP to afford the corresponding aldehyde (XXII). The condensation of aldehyde (XXII) with the known carboxylic acid (XXIII) by means of LDA in THF provides the linear adduct (XXIV), which is treated with Troc-Cl to protect the free OH group of (XXIV) yielding carboxylic acid (XXV).
| 【1】 Jung, J.-K.; Kache, R.; Vines, K.K.; Zheng, Y.-S.; Avery, M.A.; Total synthesis of epothilones B and D amenable to large-scale preparation. 225th ACS Natl Meet (March 23 2003, New Orleans) 2003, Abst MEDI 121. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 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) | 52614 | dimethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate | C7H12NO3PS | 详情 | 详情 | |
| (XIII) | 52575 | 5-bromo-2-methyl-1-pentene | C6H11Br | 详情 | 详情 | |
| (XIV) | 51602 | 1-Propyne | C3H4 | 详情 | 详情 | |
| (XV) | 63910 | 1-hexynyllithium | C6H9Li | 详情 | 详情 | |
| (XVI) | 52576 | (2,6-dimethyl-1,6-heptadienyl)(1-hexynyl)copper | C15H24Cu | 详情 | 详情 | |
| (XVII) | 52579 | 6,10-dimethyl-2-({[4-(methyloxy)phenyl]methyl}oxy)-5,10-undecadien-3-ol | C21H32O3 | 详情 | 详情 | |
| (XVIII) | 54299 | (3R,4S)-4-[(2Z)-3,7-dimethyl-2,7-octadienyl]-1-(4-methoxyphenyl)-3,10,10-trimethyl-2,5,7-trioxa-10-silaundecane; 4-{(3R,4S)-4-[(2Z)-3,7-dimethyl-2,7-octadienyl]-3,10,10-trimethyl-2,5,7-trioxa-10-silaundec-1-yl}phenyl methyl ether | n/a | C27H46O4Si | 详情 | 详情 |
| (XIX) | 54301 | (3S,5Z)-6,10-dimethyl-3-{[2-(trimethylsilyl)ethoxy]methoxy}-5,10-undecadien-2-one | n/a | C19H36O3Si | 详情 | 详情 |
| (XX) | 54302 | 2-methyl-4-((1E,3S,5Z)-2,6,10-trimethyl-3-{[2-(trimethylsilyl)ethoxy]methoxy}-1,5,10-undecatrienyl)-1,3-thiazole; (1S,3Z)-4,8-dimethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3,8-nonadienyl [2-(trimethylsilyl)ethoxy]methyl ether | n/a | C24H41NO2SSi | 详情 | 详情 |
| (XXI) | 54303 | (2S,6Z,9S,10E)-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-9-{[2-(trimethylsilyl)ethoxy]methoxy}-6,10-undecadien-1-ol | n/a | C24H43NO3SSi | 详情 | 详情 |
| (XXII) | 34304 | (2S)-3-[3-[bis(2-chloroethyl)amino]phenyl]-2-[[(2S)-3-(4-fluorophenyl)-2-(formylamino)propanoyl]amino]propionic acid | C23H26Cl2FN3O4 | 详情 | 详情 | |
| (XXIII) | 43166 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid | C15H30O4Si | 详情 | 详情 | |
| (XXIV) | 54305 | (3S,6R,7S,8S,12Z,15S,16E)-3-{[tert-butyl(dimethyl)silyl]oxy}-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-15-{[2-(trimethylsilyl)ethoxy]methoxy}-12,16-heptadecadienoic acid | n/a | C39H71NO7SSi2 | 详情 | 详情 |
| (XXV) | 54306 | (3S,6R,7S,8S,12Z,15S,16E)-3-{[tert-butyl(dimethyl)silyl]oxy}-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-7-{[(2,2,2-trichloroethoxy)carbonyl]oxy}-15-{[2-(trimethylsilyl)ethoxy]methoxy}-12,16-heptadecadienoic acid | n/a | C42H72Cl3NO9SSi2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(X)Synthesis of the target epothilone D. The condensation of 4-methyl-4-pentenyl bromide (XIII) with propyne (XIV) and 1-hexynyl lithium (XV) by means of CuBr in DMSO/ethyl ether gives the copper complex (XVI), which is condensed with the chiral epoxide (III) to yield the chiral unsaturated alcohol (XVII). The protection of the free OH group of (XVII) with Sem-Cl and DIEA in dichloromethane affords compound (XVIII). The selective cleavage of the Pmb protecting group of (XVIII) by means of DDQ, followed by oxidation of the resulting alcohol with oxalyl chloride provides the methyl ketone (XIX), which is condensed with the intermediate phosphonate (X) by means of BuLi in THF to give the adduct (XX). The hydroxylation of the terminal vinylene double bond of (XX) by means of (Ipc)2BH and LiOH yields the primary alcohol (XXI), which is oxidized with (COCl)2, PTAP or DMP to afford the corresponding aldehyde (XXII). The condensation of aldehyde (XXII) with the known carboxylic acid (XXIII) by means of LDA in THF provides the linear adduct (XXIV), which is treated with Troc-Cl to protect the free OH group of (XXIV) yielding carboxylic acid (XXV).
| 【1】 Jung, J.-K.; Kache, R.; Vines, K.K.; Zheng, Y.-S.; Avery, M.A.; Total synthesis of epothilones B and D amenable to large-scale preparation. 225th ACS Natl Meet (March 23 2003, New Orleans) 2003, Abst MEDI 121. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 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) | 52614 | dimethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate | C7H12NO3PS | 详情 | 详情 | |
| (XIII) | 52575 | 5-bromo-2-methyl-1-pentene | C6H11Br | 详情 | 详情 | |
| (XIV) | 51602 | 1-Propyne | C3H4 | 详情 | 详情 | |
| (XV) | 63910 | 1-hexynyllithium | C6H9Li | 详情 | 详情 | |
| (XVI) | 52576 | (2,6-dimethyl-1,6-heptadienyl)(1-hexynyl)copper | C15H24Cu | 详情 | 详情 | |
| (XVII) | 52579 | 6,10-dimethyl-2-({[4-(methyloxy)phenyl]methyl}oxy)-5,10-undecadien-3-ol | C21H32O3 | 详情 | 详情 | |
| (XVIII) | 54299 | (3R,4S)-4-[(2Z)-3,7-dimethyl-2,7-octadienyl]-1-(4-methoxyphenyl)-3,10,10-trimethyl-2,5,7-trioxa-10-silaundecane; 4-{(3R,4S)-4-[(2Z)-3,7-dimethyl-2,7-octadienyl]-3,10,10-trimethyl-2,5,7-trioxa-10-silaundec-1-yl}phenyl methyl ether | n/a | C27H46O4Si | 详情 | 详情 |
| (XIX) | 54301 | (3S,5Z)-6,10-dimethyl-3-{[2-(trimethylsilyl)ethoxy]methoxy}-5,10-undecadien-2-one | n/a | C19H36O3Si | 详情 | 详情 |
| (XX) | 54302 | 2-methyl-4-((1E,3S,5Z)-2,6,10-trimethyl-3-{[2-(trimethylsilyl)ethoxy]methoxy}-1,5,10-undecatrienyl)-1,3-thiazole; (1S,3Z)-4,8-dimethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3,8-nonadienyl [2-(trimethylsilyl)ethoxy]methyl ether | n/a | C24H41NO2SSi | 详情 | 详情 |
| (XXI) | 54303 | (2S,6Z,9S,10E)-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-9-{[2-(trimethylsilyl)ethoxy]methoxy}-6,10-undecadien-1-ol | n/a | C24H43NO3SSi | 详情 | 详情 |
| (XXII) | 34304 | (2S)-3-[3-[bis(2-chloroethyl)amino]phenyl]-2-[[(2S)-3-(4-fluorophenyl)-2-(formylamino)propanoyl]amino]propionic acid | C23H26Cl2FN3O4 | 详情 | 详情 | |
| (XXIII) | 43166 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid | C15H30O4Si | 详情 | 详情 | |
| (XXIV) | 54305 | (3S,6R,7S,8S,12Z,15S,16E)-3-{[tert-butyl(dimethyl)silyl]oxy}-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-15-{[2-(trimethylsilyl)ethoxy]methoxy}-12,16-heptadecadienoic acid | n/a | C39H71NO7SSi2 | 详情 | 详情 |
| (XXV) | 54306 | (3S,6R,7S,8S,12Z,15S,16E)-3-{[tert-butyl(dimethyl)silyl]oxy}-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-7-{[(2,2,2-trichloroethoxy)carbonyl]oxy}-15-{[2-(trimethylsilyl)ethoxy]methoxy}-12,16-heptadecadienoic acid | n/a | C42H72Cl3NO9SSi2 | 详情 | 详情 |