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【结 构 式】 
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【分子编号】43176 【品名】(4S,7R,8S,9S,16S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione 【CA登记号】 |
【 分 子 式 】C32H53NO5SSi 【 分 子 量 】591.92806 【元素组成】C 64.93% H 9.02% N 2.37% O 13.51% S 5.42% Si 4.74% |
合成路线1
该中间体在本合成路线中的序号：(XII)Butane-1,4-diol (II) is anchored to chloromethyl-RESIN (I) by means of tetrabutylammonium iodide and NaH in DMF, and without isolation is treated with PPh3 I2 and imidazole to yield the phosphonium salt (III), which is treated with NaHMDS in THF/DMSO, affording the phosphorane (IV). The condensation of (IV) with the chiral aldehyde (V) in THF provides the anchored olefin (VI), which is desilylated with HF in pyridine/THF. The resulting alcohol is submitted to a Swern oxidation to give the anchored aldehyde (VII). The condensation of (VII) with the ketoacid (VIII) by means of LDA and ZnCl2 in THF yields the adduct (IX) as a diastereomeric mixture. The esterification of carboxylic acid (IX) with the alcohol (X) by means of DCC and DMAP affords the corresponding ester (XI), which is submitted to a macrocyclic ring-closing metathesis catalyzed by a ruthenium catalyst providing, after chromatographic separation of isomers, the macrocyclic lactone (XII). The desilylation of (XII) by means of TFA in dichloromethane gives the precursor (XIII), which is finally epoxidated with methyl(trifluoromethyl)dioxirane (XI) to yield the target epothilone A.
| 【1】 Park, K.-H.; Kurth, M.J.; Cyclo-elimination release strategies applied to solid-phase organic synthesis in drug discovery. Drugs Fut 2000, 25, 12, 1265. |
| 【2】 Nicolaou, K.C.; et al.; Synthesis of epothilones A and B in solid and solution phase. Nature 1997, 387, 6630, 268. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IXa) | 43167 | (3S,6S,7S,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoic acid | C27H52O6Si | 详情 | 详情 | |
| (IXb) | 43168 | (3S,6R,7S,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoic acid | C27H52O6Si | 详情 | 详情 | |
| (IXc) | 43169 | (3S,6R,7R,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoic acid | C27H52O6Si | 详情 | 详情 | |
| (IXd) | 43170 | (3S,6S,7R,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoic acid | C27H52O6Si | 详情 | 详情 | |
| (XIa) | 43172 | (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6S,7S,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoate | C38H65NO6SSi | 详情 | 详情 | |
| (XIb) | 43173 | (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6S,7R,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoate | C38H65NO6SSi | 详情 | 详情 | |
| (XIc) | 43174 | (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6R,7R,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoate | C38H65NO6SSi | 详情 | 详情 | |
| (XId) | 43175 | (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6R,7S,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoate | C38H65NO6SSi | 详情 | 详情 | |
| (II) | 43160 | 1,4-butanediol;1,4-Dihydroxybutane;1,4-Butylene glycol;Tetramethylene glycol | 110-63-4 | C4H10O2 | 详情 | 详情 |
| (III) | 43161 | (4-methoxybutyl)(triphenyl)phosphonium iodide | C23H26IOP | 详情 | 详情 | |
| (IV) | 43162 | (4-methoxybutylidene)(triphenyl)phosphorane; methyl 4-(triphenylphosphoranylidene)butyl ether | C23H25OP | 详情 | 详情 | |
| (V) | 43163 | (5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-5-methylhexanal | C13H28O2Si | 详情 | 详情 | |
| (VI) | 43164 | tert-butyl(dimethyl)silyl (2S,6Z)-10-methoxy-2-methyl-6-decenyl ether; tert-butyl[[(2S,6Z)-10-methoxy-2-methyl-6-decenyl]oxy]dimethylsilane | C18H38O2Si | 详情 | 详情 | |
| (VII) | 43165 | (2S,6Z)-10-methoxy-2-methyl-6-decenal | C12H22O2 | 详情 | 详情 | |
| (VIII) | 43166 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid | C15H30O4Si | 详情 | 详情 | |
| (X) | 43171 | (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol | C11H15NOS | 详情 | 详情 | |
| (XII) | 43176 | (4S,7R,8S,9S,16S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C32H53NO5SSi | 详情 | 详情 | |
| (XIII) | 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 | |
| (XIV) | 43177 | 3-methyl-3-(trifluoromethyl)-1,2-dioxirane | C3H3F3O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XV)The reduction of 2-methylthiazole-4-carboxylic acid ethyl ester (IX) with DIBAL in dichloromethane gives the corresponding aldehyde (X), which is condensed with the phosphorane (XI) in refluxing benzene to yield 2-methyl-3-(2-methylthiazol-4-yl)-2-propenal (XII). The alkylation of (XII) with (+)-diisopinocampheyl(allyl)borane (II) in ethyl ether affords the chiral secondary alcohol (XIII) (1), which is esterified with the intermediate tridecenoic acid (VIII) by means of EDC and DMAP in dichloromethane to provide the ester (XIV). Ring-closing metathesis of (XIV) catalyzed by a Ru catalyst gives the macrolactone (XV), which is desilylated by means of TFA in dichloromethane, yielding the dihydroxymacrolactone (XVI). Finally, the double bond of (XVI) is epoxidized by means of dimethyldioxirane (DMDO) or MCPBA in chloroform.
| 【1】 Nicolaou, K.C.; et al.; The olefin metathesis approach to epothilone A and its analogues. J Am Chem Soc 1997, 119, 34, 7960. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 44449 | allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane | C23H39B | 详情 | 详情 | |
| (VIII) | 44453 | (3S,6R,7S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid | C23H44O5Si | 详情 | 详情 | |
| (IX) | 44454 | ethyl 2-methyl-1,3-thiazole-4-carboxylate | 6436-59-5 | C7H9NO2S | 详情 | 详情 |
| (X) | 44455 | 2-methyl-1,3-thiazole-4-carbaldehyde | C5H5NOS | 详情 | 详情 | |
| (XI) | 39940 | 2-(triphenylphosphoranylidene)propanal | C21H19OP | 详情 | 详情 | |
| (XII) | 44456 | (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal | C8H9NOS | 详情 | 详情 | |
| (XIII) | 43171 | (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol | C11H15NOS | 详情 | 详情 | |
| (XIV) | 44457 | (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6R,7S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8-tetramethyl-5-oxo-12-tridecenoate | C34H57NO5SSi | 详情 | 详情 | |
| (XV) | 43176 | (4S,7R,8S,9S,16S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C32H53NO5SSi | 详情 | 详情 | |
| (XVI) | 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3
该中间体在本合成路线中的序号：(XXXVIII)The Yamaguchi macrolactonization of (XXXVI) by means of 2,4,6-trichlorobenzoyl chloride and TEA in THF gives the macrolactone (XXXVII), which is debenzylated with DDQ, yielding (XXXVIII) and desilylated with TFA to afford the dihydroxylactone (XXXIX). Finally, this compound is epoxidated by means of H2O2 and acetonitrile in methanol/water.
| 【1】 Panek, J.S.; Zhu, B.; Total synthesis of apothilone A. Org Lett 2000, 2, 17, 2575. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXVI) | 44502 | (3S,6R,7S,8S,12Z,15S,16E)-7-(benzyloxy)-3-[[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 | C39H61NO6SSi | 详情 | 详情 | |
| (XXXVII) | 44503 | (4S,7R,8S,9S,16S)-8-(benzyloxy)-4-[[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 | C39H59NO5SSi | 详情 | 详情 | |
| (XXXVIII) | 43176 | (4S,7R,8S,9S,16S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C32H53NO5SSi | 详情 | 详情 | |
| (XXXIX) | 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4
该中间体在本合成路线中的序号：(XXXIII)The Suzuki coupling of the unsaturated ketoester (XXIX) with the omega iodoalkyl thiazole intermediate (XII) by means of PdCl2(dppf)2, AsPh3, Cs2CO3 and 9-BBN gives the heptadienoic ester (XXX), which is treated with MeONa, Tms-OTf and NaOH to yield the hydroxyacid (XXXI). The macrocyclization of (XXXI) under Yamaguchi conditions affords the macrolactone (XXXII), which is treated with DDQ (cleavage of the Pmb group) to provide the still silylated compound (XXXIII). The treatment of (XXXIII) with HF and pyridine (cleavage of the Tbdms group) gives the free macrolactone (XXXIV), which is finally epoxidated by means of DMDO to furnish the target epothilone A.
| 【1】 Wong, C.-H.; Liu, J.; Aldolase-catalyzed asymmetric synthesis of novel pyranose synthons as a new entry to heterocycles and epothilones. Angew Chem. Int Ed 2002, 41, 8, 1404. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 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 | |
| (XXIX) | 54281 | tert-butyl (3S,6R,7S,8S)-3-{[tert-butyl(dimethyl)silyl]oxy}-7-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-5-oxo-10-undecenoate | n/a | C33H56O6Si | 详情 | 详情 |
| (XXX) | 54282 | tert-butyl (3S,6R,7S,8S,12Z,15S,16E)-15-(acetyloxy)-3-{[tert-butyl(dimethyl)silyl]oxy}-7-[(4-methoxybenzyl)oxy]-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate | n/a | C46H73NO8SSi | 详情 | 详情 |
| (XXXI) | 54283 | (3S,6R,7S,8S,12Z,15S,16E)-3-{[tert-butyl(dimethyl)silyl]oxy}-15-hydroxy-7-[(4-methoxybenzyl)oxy]-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid | n/a | C40H63NO7SSi | 详情 | 详情 |
| (XXXII) | 54284 | (4S,7R,8S,9S,16S)-4-{[tert-butyl(dimethyl)silyl]oxy}-8-[(4-methoxybenzyl)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 | n/a | C40H61NO6SSi | 详情 | 详情 |
| (XXXIII) | 43176 | (4S,7R,8S,9S,16S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C32H53NO5SSi | 详情 | 详情 | |
| (XXXIV) | 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5
该中间体在本合成路线中的序号：(XV)The reduction of 2-methylthiazole-4-carboxylic acid ethyl ester (IX) with DIBAL in dichloromethane gives the corresponding aldehyde (X), which is condensed with the phosphorane (XI) in refluxing benzene to yield 2-methyl-3-(2-methylthiazol-4-yl)-2-propenal (XII). The alkylation of (XII) with (+)-diisopinocampheyl(allyl)borane (II) in ethyl ether affords the chiral secondary alcohol (XIII) (1), which is esterified with the intermediate tridecenoic acid (VIII) by means of EDC and DMAP in dichloromethane to provide the ester (XIV). Ring-closing metathesis of (XIV) catalyzed by a Ru catalyst gives the macrolactone (XV), which is finally desilylated by means of TFA in dichloromethane, yielding the target epothilone C.
| 【1】 Nicolaou, K.C.; et al.; The olefin metathesis approach to epothilone A and its analogues. J Am Chem Soc 1997, 119, 34, 7960. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 44449 | allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane | C23H39B | 详情 | 详情 | |
| (VIII) | 44453 | (3S,6R,7S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid | C23H44O5Si | 详情 | 详情 | |
| (IX) | 44454 | ethyl 2-methyl-1,3-thiazole-4-carboxylate | 6436-59-5 | C7H9NO2S | 详情 | 详情 |
| (X) | 44455 | 2-methyl-1,3-thiazole-4-carbaldehyde | C5H5NOS | 详情 | 详情 | |
| (XI) | 39940 | 2-(triphenylphosphoranylidene)propanal | C21H19OP | 详情 | 详情 | |
| (XII) | 44456 | (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal | C8H9NOS | 详情 | 详情 | |
| (XIII) | 43171 | (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol | C11H15NOS | 详情 | 详情 | |
| (XIV) | 44457 | (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6R,7S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8-tetramethyl-5-oxo-12-tridecenoate | C34H57NO5SSi | 详情 | 详情 | |
| (XV) | 43176 | (4S,7R,8S,9S,16S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C32H53NO5SSi | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XXXVIII)The Yamauchi macrolactonization of (XXXVI) by means of 2,4,6-trichlorobenzoyl chloride and TEA in THF gives the macrolactone (XXXVII), which is debenzylated with DDQ, yielding (XXXVIII), finally desilylated with TFA to afford the target epothilone C.
| 【1】 Panek, J.S.; Zhu, B.; Total synthesis of apothilone A. Org Lett 2000, 2, 17, 2575. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXVI) | 44502 | (3S,6R,7S,8S,12Z,15S,16E)-7-(benzyloxy)-3-[[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 | C39H61NO6SSi | 详情 | 详情 | |
| (XXXVII) | 44503 | (4S,7R,8S,9S,16S)-8-(benzyloxy)-4-[[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 | C39H59NO5SSi | 详情 | 详情 | |
| (XXXVIII) | 43176 | (4S,7R,8S,9S,16S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C32H53NO5SSi | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XII)Butane-1,4-diol (II) is anchored to chloromethyl-RESIN (I) by means of tetrabutylammonium iodide and NaH in DMF, and without isolation is treated with PPh3 I2 and imidazole to yield the phosphonium salt (III), which is treated with NaHMDS in THF/DMSO, affording the phosphorane (IV). The condensation of (IV) with the chiral aldehyde (V) in THF provides the anchored olefin (VI), which is desilylated with HF in pyridine/THF. The resulting alcohol is submitted to a Swern oxidation to give the anchored aldehyde (VII). The condensation of (VII) with the ketoacid (VIII) by means of LDA and ZnCl2 in THF yields the adduct (IX) as a diastereomeric mixture. The esterification of carboxylic acid (IX) with the alcohol (X) by means of DCC and DMAP affords the corresponding ester (XI), which is submitted to a macrocyclic ring-closing metathesis catalyzed by a ruthenium catalyst providing, after chromatographic separation of isomers, the macrocyclic lactone (XII). Compound (XII) is finally desilylated by means of TFA in dichloromethane to give the target epothilone C.
| 【1】 Park, K.-H.; Kurth, M.J.; Cyclo-elimination release strategies applied to solid-phase organic synthesis in drug discovery. Drugs Fut 2000, 25, 12, 1265. |
| 【2】 Nicolaou, K.C.; et al.; Synthesis of epothilones A and B in solid and solution phase. Nature 1997, 387, 6630, 268. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IXa) | 43167 | (3S,6S,7S,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoic acid | C27H52O6Si | 详情 | 详情 | |
| (IXb) | 43168 | (3S,6R,7S,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoic acid | C27H52O6Si | 详情 | 详情 | |
| (IXc) | 43169 | (3S,6R,7R,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoic acid | C27H52O6Si | 详情 | 详情 | |
| (IXd) | 43170 | (3S,6S,7R,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoic acid | C27H52O6Si | 详情 | 详情 | |
| (XIa) | 43172 | (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6S,7S,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoate | C38H65NO6SSi | 详情 | 详情 | |
| (XIb) | 43173 | (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6S,7R,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoate | C38H65NO6SSi | 详情 | 详情 | |
| (XIc) | 43174 | (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6R,7R,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoate | C38H65NO6SSi | 详情 | 详情 | |
| (XId) | 43175 | (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6R,7S,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoate | C38H65NO6SSi | 详情 | 详情 | |
| (II) | 43160 | 1,4-butanediol;1,4-Dihydroxybutane;1,4-Butylene glycol;Tetramethylene glycol | 110-63-4 | C4H10O2 | 详情 | 详情 |
| (III) | 43161 | (4-methoxybutyl)(triphenyl)phosphonium iodide | C23H26IOP | 详情 | 详情 | |
| (IV) | 43162 | (4-methoxybutylidene)(triphenyl)phosphorane; methyl 4-(triphenylphosphoranylidene)butyl ether | C23H25OP | 详情 | 详情 | |
| (V) | 43163 | (5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-5-methylhexanal | C13H28O2Si | 详情 | 详情 | |
| (VI) | 43164 | tert-butyl(dimethyl)silyl (2S,6Z)-10-methoxy-2-methyl-6-decenyl ether; tert-butyl[[(2S,6Z)-10-methoxy-2-methyl-6-decenyl]oxy]dimethylsilane | C18H38O2Si | 详情 | 详情 | |
| (VII) | 43165 | (2S,6Z)-10-methoxy-2-methyl-6-decenal | C12H22O2 | 详情 | 详情 | |
| (VIII) | 43166 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid | C15H30O4Si | 详情 | 详情 | |
| (X) | 43171 | (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol | C11H15NOS | 详情 | 详情 | |
| (XII) | 43176 | (4S,7R,8S,9S,16S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C32H53NO5SSi | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XXXIII)The Suzuki coupling of the unsaturated ketoester (XXIX) with the omega iodoalkyl thiazole intermediate (XII) by means of PdCl2(dppf)2, AsPh3, Cs2CO3 and 9-BBN gives the heptadienoic ester (XXX), which is treated with MeONa, Tms-OTf and NaOH to yield the hydroxyacid (XXXI). The macrocyclization of (XXXI) under Yamaguchi conditions affords the macrolactone (XXXII), which is treated with DDQ (cleavage of the Pmb group) to provide the still silylated compound (XXXIII). Finally, the treatment of (XXXIII) with HF and pyridine (cleavage of the Tbdms group) gives the the target epothilone C.
| 【1】 Wong, C.-H.; Liu, J.; Aldolase-catalyzed asymmetric synthesis of novel pyranose synthons as a new entry to heterocycles and epothilones. Angew Chem. Int Ed 2002, 41, 8, 1404. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 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 | |
| (XXIX) | 54281 | tert-butyl (3S,6R,7S,8S)-3-{[tert-butyl(dimethyl)silyl]oxy}-7-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-5-oxo-10-undecenoate | n/a | C33H56O6Si | 详情 | 详情 |
| (XXX) | 54282 | tert-butyl (3S,6R,7S,8S,12Z,15S,16E)-15-(acetyloxy)-3-{[tert-butyl(dimethyl)silyl]oxy}-7-[(4-methoxybenzyl)oxy]-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate | n/a | C46H73NO8SSi | 详情 | 详情 |
| (XXXI) | 54283 | (3S,6R,7S,8S,12Z,15S,16E)-3-{[tert-butyl(dimethyl)silyl]oxy}-15-hydroxy-7-[(4-methoxybenzyl)oxy]-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid | n/a | C40H63NO7SSi | 详情 | 详情 |
| (XXXII) | 54284 | (4S,7R,8S,9S,16S)-4-{[tert-butyl(dimethyl)silyl]oxy}-8-[(4-methoxybenzyl)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 | n/a | C40H61NO6SSi | 详情 | 详情 |
| (XXXIII) | 43176 | (4S,7R,8S,9S,16S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C32H53NO5SSi | 详情 | 详情 |