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【结 构 式】 
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【分子编号】54281 【品名】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 【CA登记号】n/a |
【 分 子 式 】C33H56O6Si 【 分 子 量 】576.88954 【元素组成】C 68.71% H 9.78% O 16.64% Si 4.87% |
合成路线1
该中间体在本合成路线中的序号：(XXIX)The oxidation of the lactol (XIII) with Br2 and BaCO3 gives the lactone (XIV), which is stereoselectively alkylated with allyl bromide (XV) by means of LDA in HMPA to yield lactone (XVI). The opening of the lactone ring of (XVI) with MeONa affords the dihydroxyester (XVII), which is protected by reaction with anisaldehyde dimethylacetal (XVIII) and CSA to provide the benzylidene derivative (XIX). The reduction of the ester group of (XIX) with LiAlH4 gives the corresponding carbinol (XX), which is acylated with Ms-Cl and TEA to yield the mesylate (XXI). The reduction of the mesyloxy group of (XXI) with LiAlH4 affords the dimethyl compound (XXII), which is submitted to a regioselective cleavage of the Pmp protecting group by means of DIBAL in toluene to provide the primary alcohol (XXIII). The oxidation of (XXIII) with DMP gives the corresponding aldehyde (XXIV), which is condensed with tert-butyl isobutyrylacetate (XXV) by means of NaH and BuLi to yield the unsaturated ketoester (XXVI). Stereoselective reduction of the beta-oxo group of (XXVI) by means of Me4NBH(OAc)3 affords the desired diol (XXVII), which is regioselectively silylated at the beta-hydroxy group by means of Tbdms-OTf to provide the monosilyl ether (XXVIII). The oxidation of the remaining hydroxy group of (XXVIII) by means of DMP gives the unsaturated ketoester (XXIX).
| 【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 |
|---|---|---|---|---|---|---|
| (XIII) | 54267 | (4S,5S)-5-methyltetrahydro-2H-pyran-2,4-diol | C6H12O3 | 详情 | 详情 | |
| (XIV) | 54268 | (4S,5S)-4-hydroxy-5-methyltetrahydro-2H-pyran-2-one | C6H10O3 | 详情 | 详情 | |
| (XV) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (XVI) | 54269 | (3S,4R,5S)-3-allyl-4-hydroxy-5-methyltetrahydro-2H-pyran-2-one | C9H14O3 | 详情 | 详情 | |
| (XVII) | 54270 | methyl (2S)-2-[(1R,2S)-1,3-dihydroxy-2-methylpropyl]-4-pentenoate | C10H18O4 | 详情 | 详情 | |
| (XVIII) | 26485 | 1-(dimethoxymethyl)-4-methoxybenzene | 2186-92-7 | C10H14O3 | 详情 | 详情 |
| (XIX) | 54271 | methyl (2S)-2-[(4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-4-pentenoate | n/a | C18H24O5 | 详情 | 详情 |
| (XX) | 54272 | (2R)-2-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-4-penten-1-ol | n/a | C17H24O4 | 详情 | 详情 |
| (XXI) | 54273 | (2R)-2-[(4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-4-pentenyl methanesulfonate | n/a | C18H26O6S | 详情 | 详情 |
| (XXII) | 54274 | (4S,5S)-2-(4-methoxyphenyl)-5-methyl-4-[(1S)-1-methyl-3-butenyl]-1,3-dioxane; methyl 4-{(4S,5S)-5-methyl-4-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-2-yl}phenyl ether | n/a | C17H24O3 | 详情 | 详情 |
| (XXIII) | 54275 | (2S,3S,4S)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-6-hepten-1-ol | n/a | C17H26O3 | 详情 | 详情 |
| (XXIV) | 54276 | (2R,3S,4S)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-6-heptenal | n/a | C17H24O3 | 详情 | 详情 |
| (XXV) | 54277 | tert-butyl 4-methyl-3-oxopentanoate | 94250-54-1 | C10H18O3 | 详情 | 详情 |
| (XXVI) | 54278 | tert-butyl (5S,6S,7S,8S)-5-hydroxy-7-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-3-oxo-10-undecenoate | n/a | C27H42O6 | 详情 | 详情 |
| (XXVII) | 54279 | tert-butyl (3S,5S,6S,7S,8S)-3,5-dihydroxy-7-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-10-undecenoate | n/a | C27H44O6 | 详情 | 详情 |
| (XXVIII) | 54280 | tert-butyl (3S,5S,6S,7S,8S)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-hydroxy-7-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-10-undecenoate | n/a | C33H58O6Si | 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 |
合成路线2
该中间体在本合成路线中的序号：(XXIX)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3
该中间体在本合成路线中的序号：(XXIX)The oxidation of the lactol (XIII) with Br2 and BaCO3 gives the lactone (XIV), which is stereoselectively alkylated with allyl bromide (XV) by means of LDA in HMPA to yield lactone (XVI). The opening of the lactone ring of (XVI) with MeONa affords the dihydroxyester (XVII), which is protected by reaction with anisaldehyde dimethylacetal (XVIII) and CSA to provide the benzylidene derivative (XIX). The reduction of the ester group of (XIX) with LiAlH4 gives the corresponding carbinol (XX), which is acylated with Ms-Cl and TEA to yield the mesylate (XXI). The reduction of the mesyloxy group of (XXI) with LiAlH4 affords the dimethyl compound (XXII), which is submitted to a regioselective cleavage of the Pmp protecting group by means of DIBAL in toluene to provide the primary alcohol (XXIII). The oxidation of (XXIII) with DMP gives the corresponding aldehyde (XXIV), which is condensed with tert-butyl isobutyrylacetate (XXV) by means of NaH and BuLi to yield the unsaturated ketoester (XXVI). Stereoselective reduction of the beta-oxo group of (XXVI) by means of Me4NBH(OAc)3 affords the desired diol (XXVII), which is regioselectively silylated at the beta-hydroxy group by means of Tbdms-OTf to provide the monosilyl ether (XXVIII). The oxidation of the remaining hydroxy group of (XXVIII) by means of DMP gives the unsaturated ketoester (XXIX).
| 【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 |
|---|---|---|---|---|---|---|
| (XIII) | 54267 | (4S,5S)-5-methyltetrahydro-2H-pyran-2,4-diol | C6H12O3 | 详情 | 详情 | |
| (XIV) | 54268 | (4S,5S)-4-hydroxy-5-methyltetrahydro-2H-pyran-2-one | C6H10O3 | 详情 | 详情 | |
| (XV) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (XVI) | 54269 | (3S,4R,5S)-3-allyl-4-hydroxy-5-methyltetrahydro-2H-pyran-2-one | C9H14O3 | 详情 | 详情 | |
| (XVII) | 54270 | methyl (2S)-2-[(1R,2S)-1,3-dihydroxy-2-methylpropyl]-4-pentenoate | C10H18O4 | 详情 | 详情 | |
| (XVIII) | 26485 | 1-(dimethoxymethyl)-4-methoxybenzene | 2186-92-7 | C10H14O3 | 详情 | 详情 |
| (XIX) | 54271 | methyl (2S)-2-[(4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-4-pentenoate | n/a | C18H24O5 | 详情 | 详情 |
| (XX) | 54272 | (2R)-2-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-4-penten-1-ol | n/a | C17H24O4 | 详情 | 详情 |
| (XXI) | 54273 | (2R)-2-[(4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-4-pentenyl methanesulfonate | n/a | C18H26O6S | 详情 | 详情 |
| (XXII) | 54274 | (4S,5S)-2-(4-methoxyphenyl)-5-methyl-4-[(1S)-1-methyl-3-butenyl]-1,3-dioxane; methyl 4-{(4S,5S)-5-methyl-4-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-2-yl}phenyl ether | n/a | C17H24O3 | 详情 | 详情 |
| (XXIII) | 54275 | (2S,3S,4S)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-6-hepten-1-ol | n/a | C17H26O3 | 详情 | 详情 |
| (XXIV) | 54276 | (2R,3S,4S)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-6-heptenal | n/a | C17H24O3 | 详情 | 详情 |
| (XXV) | 54277 | tert-butyl 4-methyl-3-oxopentanoate | 94250-54-1 | C10H18O3 | 详情 | 详情 |
| (XXVI) | 54278 | tert-butyl (5S,6S,7S,8S)-5-hydroxy-7-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-3-oxo-10-undecenoate | n/a | C27H42O6 | 详情 | 详情 |
| (XXVII) | 54279 | tert-butyl (3S,5S,6S,7S,8S)-3,5-dihydroxy-7-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-10-undecenoate | n/a | C27H44O6 | 详情 | 详情 |
| (XXVIII) | 54280 | tert-butyl (3S,5S,6S,7S,8S)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-hydroxy-7-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-10-undecenoate | n/a | C33H58O6Si | 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 |
合成路线4
该中间体在本合成路线中的序号：(XXIX)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 |