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【结 构 式】 
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【分子编号】52578 【品名】methyl 4-({[1-(2-oxiranyl)ethyl]oxy}methyl)phenyl ether; 2-[1-({[4-(methyloxy)phenyl]methyl}oxy)ethyl]oxirane 【CA登记号】 |
【 分 子 式 】C2H5NS 【 分 子 量 】75.13444 【元素组成】C 31.97% H 6.71% N 18.64% S 42.68% |
合成路线1
该中间体在本合成路线中的序号：(IX)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：(III)The reaction of 4-methyl-4-penten-1-ol (I) with PBr3 gives the corresponding alkyl bromide (II), which is condensed with epoxide (III) and propyne (IV) by means of Mg, CuI and pentynyl lithium to yield, after silylation with Tbdms-Cl, the protected diol (V). The selective deprotection of (V) with DDQ gives the secondary alcohol (VI), which is oxidized by the Swern reagent to afford the ketone (VII). Alternatively, ketone (VII) can also be obtained by direct oxidation of the protected diol (V) with the Jones reagent. The Horner Emmons condensation of ketone (VII) with phosphonate (VIII) provides the unsaturated alkyl thiazole (IX), which is treated with (Ipc)2BH and sodium formate in THF to give the secondary alcohol (X). The oxidation of (X) with the complex SO3/Pyr yields the carbaldehyde (XI). Alternatively, (XI) can also be obtained by direct oxidation of the terminal double bond of (IX) with (Ipc)2BH and pyridinium chlorochromate (PCC). The condensation of aldehyde (XI) with ketoacid (XII) by means of LDA in THF affords the heptadecadienoic acid (XIII), which is silylated with Tbdms-OTf to provide the protected linear precursor (XIV). The cyclization of (XIV) by means of 2,4,6-trichlorobenzoyl chloride and DMAP in pyridine gives the protected cyclic precursor (XV), which is desilylated by means of TBAF in THF to yield the unprotected precursor (XVI). Finally, this compound is epoxidated by means of dimethyldioxirane (DMDO) in acetone to afford the target epothilone B.
| 【1】 Avery, M.A. (University of Mississippi); Synthesis of epothilones and related analogs. WO 0230356 . |
| 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) | 54285 | 4-methyl-4-penten-1-ol | 22508-64-1 | C6H12O | 详情 | 详情 |
| (II) | 52575 | 5-bromo-2-methyl-1-pentene | C6H11Br | 详情 | 详情 | |
| (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 | |
| (IV) | 51602 | 1-Propyne | C3H4 | 详情 | 详情 | |
| (V) | 54286 | tert-butyl(dimethyl)silyl (1S,3Z)-1-{(1R)-1-[(4-methoxybenzyl)oxy]ethyl}-4,8-dimethyl-3,8-nonadienyl ether; tert-butyl[((1S,3Z)-1-{(1R)-1-[(4-methoxybenzyl)oxy]ethyl}-4,8-dimethyl-3,8-nonadienyl)oxy]dimethylsilane | n/a | C27H46O3Si | 详情 | 详情 |
| (VI) | 54287 | (2R,3S,5Z)-3-{[tert-butyl(dimethyl)silyl]oxy}-6,10-dimethyl-5,10-undecadien-2-ol | n/a | C19H38O2Si | 详情 | 详情 |
| (VII) | 54288 | (3S,5Z)-3-{[tert-butyl(dimethyl)silyl]oxy}-6,10-dimethyl-5,10-undecadien-2-one | n/a | C19H36O2Si | 详情 | 详情 |
| (VIII) | 44442 | diethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate | C9H16NO3PS | 详情 | 详情 | |
| (IX) | 54289 | tert-butyl(dimethyl)silyl (1S,3Z)-4,8-dimethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3,8-nonadienyl ether; 4-((1E,3S,5Z)-3-{[tert-butyl(dimethyl)silyl]oxy}-2,6,10-trimethyl-1,5,10-undecatrienyl)-2-methyl-1,3-thiazole | n/a | C24H41NOSSi | 详情 | 详情 |
| (X) | 40828 | (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadien-1-ol | C24H43NO2SSi | 详情 | 详情 | |
| (XI) | 40829 | (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal | C24H41NO2SSi | 详情 | 详情 | |
| (XII) | 43166 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid | C15H30O4Si | 详情 | 详情 | |
| (XIII) | 46118 | (3S,6R,7S,8S,12Z,15S,16E)-3,15-bis[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid | C39H71NO6SSi2 | 详情 | 详情 | |
| (XIV) | 40834 | (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-heptadecadienoic acid | C45H85NO6SSi3 | 详情 | 详情 | |
| (XV) | 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 | |
| (XVI) | 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3
该中间体在本合成路线中的序号：(II)The condensation of alkyl bromide (I) with epoxide (II) and propyne (III) by means of Mg, CuI and pentynyl lithium gives the secondary alcohol (IV), which is silylated with Sem-Cl to yield the protected diol (V). The selective deprotection of (V) with DDQ gives the secondary alcohol (VI), which is oxidized by means of SO3 /pyridine to afford the ketone (VII). The condensation of ketone (VII) with phosphonate (VIII) by means of BuLi in THF provides the unsaturated alkyl thiazole (IX), which is treated with (Ipc)2BH and sodium formate in THF to give the secondary alcohol (X). The oxidation of (X) with oxalyl chloride yields the carbaldehyde (XI), which is condensed with ketoacid (XII) by means of LDA in THF to afford the heptadecadienoic acid (XIII). The protection of the free OH group of (XIII) with Troc-Cl and DMAP in dichloromethane provides the protected linear precursor (XIV), which is selectively monodeprotected with TFA in dichloromethane to furnish the linear hydroxyacid (XV). The macrocyclization of (XV) by means of 2,4,6-trichlorobenzoyl chloride and DMAP in pyridine gives the protected cyclic precursor (XVI), which is deprotected first with HF and pyridine (desilylation), and then with Zn and HOAc (elimination of the Troc protecting group), to yield the unprotected precursor (XVII). Finally, this compound is epoxidated by means of dimethyldioxirane (DMDO) in acetone to afford the target epothilone B.
| 【1】 Avery, M.A. (University of Mississippi); Synthesis of epothilones and related analogs. WO 0230356 . |
| 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) | 52575 | 5-bromo-2-methyl-1-pentene | C6H11Br | 详情 | 详情 | |
| (II) | 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 | |
| (III) | 51602 | 1-Propyne | C3H4 | 详情 | 详情 | |
| (IV) | 54286 | tert-butyl(dimethyl)silyl (1S,3Z)-1-{(1R)-1-[(4-methoxybenzyl)oxy]ethyl}-4,8-dimethyl-3,8-nonadienyl ether; tert-butyl[((1S,3Z)-1-{(1R)-1-[(4-methoxybenzyl)oxy]ethyl}-4,8-dimethyl-3,8-nonadienyl)oxy]dimethylsilane | n/a | C27H46O3Si | 详情 | 详情 |
| (V) | 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 |
| (VI) | 54300 | (2R,3S,5Z)-6,10-dimethyl-3-{[2-(trimethylsilyl)ethoxy]methoxy}-5,10-undecadien-2-ol | n/a | C19H38O3Si | 详情 | 详情 |
| (VII) | 54301 | (3S,5Z)-6,10-dimethyl-3-{[2-(trimethylsilyl)ethoxy]methoxy}-5,10-undecadien-2-one | n/a | C19H36O3Si | 详情 | 详情 |
| (VIII) | 44442 | diethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate | C9H16NO3PS | 详情 | 详情 | |
| (IX) | 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 |
| (X) | 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 |
| (XI) | 54304 | (2S,6Z,9S,10E)-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-9-{[2-(trimethylsilyl)ethoxy]methoxy}-6,10-undecadienal | n/a | C24H41NO3SSi | 详情 | 详情 |
| (XII) | 43166 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid | C15H30O4Si | 详情 | 详情 | |
| (XIII) | 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 |
| (XIV) | 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 |
| (XV) | 54307 | (3S,6R,7S,8S,12Z,15S,16E)-3-{[tert-butyl(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-trichloroethoxy)carbonyl]oxy}-12,16-heptadecadienoic acid | n/a | C36H58Cl3NO8SSi | 详情 | 详情 |
| (XVI) | 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 | |
| (XVII) | 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：(III)The intermediate chiral epoxide (III) has been obtained as follows. The Sharpless epoxidation of 3-buten-2(R)-ol (I) gives the chiral epoxide (II), which is protected with Pmb-Br and NaH to yield the target epoxide intermediate (III).
| 【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. |
合成路线5
该中间体在本合成路线中的序号：(III)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6
该中间体在本合成路线中的序号：(II)The reaction of 4-methyl-4-penten-1-ol (I) with PBr3 gives the corresponding alkyl bromide (II), which is condensed with epoxide (III) and propyne (IV) by means of Mg, CuI and pentynyl lithium to yield, after silylation with Tbdms-Cl, the protected diol (V). The selective deprotection of (V) with DDQ gives the secondary alcohol (VI), which is oxidized by the Swern reagent to afford the ketone (VII). Alternatively, ketone (VII) can also be obtained by direct oxidation of the protected diol (V) with the Jones reagent. The Horner Emmons condensation of ketone (VII) with phosphonate (VIII) provides the unsaturated alkyl thiazole (IX), which is treated with (Ipc)2BH and sodium formate in THF to give the secondary alcohol (X). The oxidation of (X) with the complex SO3/Pyr yields the carbaldehyde (XI). Alternatively, (XI) can also be obtained by direct oxidation of the terminal double bond of (IX) with (Ipc)2BH and pyridinium chlorochromate (PCC). The condensation of aldehyde (XI) with ketoacid (XII) by means of LDA in THF affords the heptadecadienoic acid (XIII), which is silylated with Tbdms-OTf to provide the protected linear precursor (XIV). The cyclization of (XIV) by means of 2,4,6-trichlorobenzoyl chloride and DMAP in pyridine gives the protected cyclic precursor (XV), which is finally desilylated by means of TBAF in THF to yield the target epothilone D.
| 【1】 Avery, M.A. (University of Mississippi); Synthesis of epothilones and related analogs. WO 0230356 . |
| 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) | 52575 | 5-bromo-2-methyl-1-pentene | C6H11Br | 详情 | 详情 | |
| (II) | 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 | |
| (III) | 51602 | 1-Propyne | C3H4 | 详情 | 详情 | |
| (IV) | 54286 | tert-butyl(dimethyl)silyl (1S,3Z)-1-{(1R)-1-[(4-methoxybenzyl)oxy]ethyl}-4,8-dimethyl-3,8-nonadienyl ether; tert-butyl[((1S,3Z)-1-{(1R)-1-[(4-methoxybenzyl)oxy]ethyl}-4,8-dimethyl-3,8-nonadienyl)oxy]dimethylsilane | n/a | C27H46O3Si | 详情 | 详情 |
| (V) | 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 |
| (VI) | 54300 | (2R,3S,5Z)-6,10-dimethyl-3-{[2-(trimethylsilyl)ethoxy]methoxy}-5,10-undecadien-2-ol | n/a | C19H38O3Si | 详情 | 详情 |
| (VII) | 54301 | (3S,5Z)-6,10-dimethyl-3-{[2-(trimethylsilyl)ethoxy]methoxy}-5,10-undecadien-2-one | n/a | C19H36O3Si | 详情 | 详情 |
| (VIII) | 44442 | diethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate | C9H16NO3PS | 详情 | 详情 | |
| (IX) | 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 |
| (X) | 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 |
| (XI) | 54304 | (2S,6Z,9S,10E)-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-9-{[2-(trimethylsilyl)ethoxy]methoxy}-6,10-undecadienal | n/a | C24H41NO3SSi | 详情 | 详情 |
| (XII) | 43166 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid | C15H30O4Si | 详情 | 详情 | |
| (XIII) | 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 |
| (XIV) | 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 |
| (XV) | 54307 | (3S,6R,7S,8S,12Z,15S,16E)-3-{[tert-butyl(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-trichloroethoxy)carbonyl]oxy}-12,16-heptadecadienoic acid | n/a | C36H58Cl3NO8SSi | 详情 | 详情 |
| (XVI) | 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 |
合成路线7
该中间体在本合成路线中的序号：(III)The condensation of alkyl bromide (I) with epoxide (II) and propyne (III) by means of Mg, CuI and pentynyl lithium gives the secondary alcohol (IV), which is silylated with Sem-Cl to yield the protected diol (V). The selective deprotection of (V) with DDQ gives the secondary alcohol (VI), which is oxidized by means of SO3 /pyridine to afford the ketone (VII). The condensation of ketone (VII) with phosphonate (VIII) by means of BuLi in THF provides the unsaturated alkyl thiazole (IX), which is treated with (Ipc)2BH and sodium formate in THF to give the secondary alcohol (X). The oxidation of (X) with oxalyl chloride yields the carbaldehyde (XI), which is condensed with ketoacid (XII) by means of LDA in THF to afford the heptadecadienoic acid (XIII). The protection of the free OH group of (XIII) with Troc-Cl and DMAP in dichloromethane provides the protected linear precursor (XIV), which is selectively monodeprotected with TFA in dichloromethane to furnish the linear hydroxyacid (XV). The macrocyclization of (XV) by means of 2,4,6-trichlorobenzoyl chloride and DMAP in pyridine gives the protected cyclic precursor (XVI), which is deprotected first with HF and pyridine (desilylation), and then with Zn and HOAc (elimination of the Troc protecting group), to finally yield the target epothilone D.
| 【1】 Avery, M.A. (University of Mississippi); Synthesis of epothilones and related analogs. WO 0230356 . |
| 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) | 54285 | 4-methyl-4-penten-1-ol | 22508-64-1 | C6H12O | 详情 | 详情 |
| (II) | 52575 | 5-bromo-2-methyl-1-pentene | C6H11Br | 详情 | 详情 | |
| (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 | |
| (IV) | 51602 | 1-Propyne | C3H4 | 详情 | 详情 | |
| (V) | 54286 | tert-butyl(dimethyl)silyl (1S,3Z)-1-{(1R)-1-[(4-methoxybenzyl)oxy]ethyl}-4,8-dimethyl-3,8-nonadienyl ether; tert-butyl[((1S,3Z)-1-{(1R)-1-[(4-methoxybenzyl)oxy]ethyl}-4,8-dimethyl-3,8-nonadienyl)oxy]dimethylsilane | n/a | C27H46O3Si | 详情 | 详情 |
| (VI) | 54287 | (2R,3S,5Z)-3-{[tert-butyl(dimethyl)silyl]oxy}-6,10-dimethyl-5,10-undecadien-2-ol | n/a | C19H38O2Si | 详情 | 详情 |
| (VII) | 54288 | (3S,5Z)-3-{[tert-butyl(dimethyl)silyl]oxy}-6,10-dimethyl-5,10-undecadien-2-one | n/a | C19H36O2Si | 详情 | 详情 |
| (VIII) | 44442 | diethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate | C9H16NO3PS | 详情 | 详情 | |
| (IX) | 54289 | tert-butyl(dimethyl)silyl (1S,3Z)-4,8-dimethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3,8-nonadienyl ether; 4-((1E,3S,5Z)-3-{[tert-butyl(dimethyl)silyl]oxy}-2,6,10-trimethyl-1,5,10-undecatrienyl)-2-methyl-1,3-thiazole | n/a | C24H41NOSSi | 详情 | 详情 |
| (X) | 40828 | (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadien-1-ol | C24H43NO2SSi | 详情 | 详情 | |
| (XI) | 40829 | (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal | C24H41NO2SSi | 详情 | 详情 | |
| (XII) | 43166 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid | C15H30O4Si | 详情 | 详情 | |
| (XIII) | 46118 | (3S,6R,7S,8S,12Z,15S,16E)-3,15-bis[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid | C39H71NO6SSi2 | 详情 | 详情 | |
| (XIV) | 40834 | (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-heptadecadienoic acid | C45H85NO6SSi3 | 详情 | 详情 | |
| (XV) | 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 |
合成路线8
该中间体在本合成路线中的序号：(III)The intermediate chiral epoxide (III) has been obtained as follows. The Sharpless epoxidation of 3-buten-2(R)-ol (I) gives the chiral epoxide (II), which is protected with Pmb-Br and NaH to yield the target epoxide intermediate (III).
| 【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. |
合成路线9
该中间体在本合成路线中的序号：(III)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 |