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【结 构 式】 
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【分子编号】52596 【品名】3-hydroxy-4,4-dimethyl-5-oxoheptanoic acid 【CA登记号】 |
【 分 子 式 】C9H16O4 【 分 子 量 】188.22364 【元素组成】C 57.43% H 8.57% O 34% |
合成路线1
该中间体在本合成路线中的序号：(V)The intermediate carboxylic acid (VI) has been obtained as follows: The condensation of the chiral oxazolidinone (I) with the aldehyde (II) gives the chiral ketone (III) as the major product. The cleavage of the chiral auxiliary with LiOOH in THF yields the carboxylic acid (IV), which is deprotected with HCl in THF to afford the oxoacid (V). Finally, the OH group of (V) is silylated with Tbdms-Cl to furnish the target intermediate carboxylic acid (VI).
| 【1】 Panicker, B.; et al.; An unusual reversal of stereoselectivity in a boron mediated aldol reaction: Enantioselective synthesis of the C1-C6 segment of the epothilones. Tetrahedron 2000, 56, 40, 7859. |
| 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) | 52572 | 4-(1-methylethyl)-3-[2-(methylsulfanyl)acetyl]-1,3-oxazolidin-2-one | C9H15NO3S | 详情 | 详情 | |
| (II) | 52593 | 2-(2-ethyl-1,3-dioxolan-2-yl)-2-methylpropanal | C9H16O3 | 详情 | 详情 | |
| (III) | 52594 | 3-[4-(2-ethyl-1,3-dioxolan-2-yl)-3-hydroxy-4-methylpentanoyl]-4-(1-methylethyl)-1,3-oxazolidin-2-one | C17H29NO6 | 详情 | 详情 | |
| (IV) | 52595 | 4-(2-ethyl-1,3-dioxolan-2-yl)-3-hydroxy-4-methylpentanoic acid | C11H20O5 | 详情 | 详情 | |
| (V) | 52596 | 3-hydroxy-4,4-dimethyl-5-oxoheptanoic acid | C9H16O4 | 详情 | 详情 | |
| (VI) | 43166 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid | C15H30O4Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIII)The condensation of 3-buten-2-one (I) with the phosphonate (II) by means of LDA gives the alkylated thiazole (III), which is enantioselectively epoxidated to the chiral oxirane (V) by means of oxone and the chiral ketone (IV). Alternatively, the oxidation of the chiral epoxybutanol (VI) with CrO3 or SO3 /pyridine yields the epoxybutanone (VII), which is condensed with phosphorane (II) by means of LDA to afford the already reported chiral oxirane (V). The condensation of (V) with alkyl bromide (VIII) and propyne (IX) by means of Mg, CuBr and pentynyl lithium provides the undecatrienyl thiazole (X), which is treated with Tms-OTf in order to protect its OH group, yielding the silyl ether (XI). The oxidation of the terminal double bond of (XI) by means of (Ipc)2BH and CrO3 affords the carbaldehyde (XII), which is condensed with ketoacid (XIII) by means of LDA in THF to provide the undecadienoic acid (XIV). The cyclization of (XIV) by means of benzenesulfonyl chloride and pyridine gives the macrocyclic intermediate (XV), which is finally epoxidated by means of DMDO in acetone to furnish 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 |
|---|---|---|---|---|---|---|
| 54294 | 1-pentynyllithium | n/a | C5H7Li | 详情 | 详情 | |
| (I) | 30324 | 3-buten-2-one; methyl vinyl ketone | 78-94-4 | C4H6O | 详情 | 详情 |
| (II) | 44442 | diethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate | C9H16NO3PS | 详情 | 详情 | |
| (III) | 54290 | 2-methyl-4-[(1E)-2-methyl-1,3-butadienyl]-1,3-thiazole | n/a | C9H11NS | 详情 | 详情 |
| (IV) | 54291 | n/a | C13H20O5 | 详情 | 详情 | |
| (V) | 54293 | 2-methyl-4-{(E)-2-[(2R)oxiranyl]-1-propenyl}-1,3-thiazole | n/a | C9H11NOS | 详情 | 详情 |
| (VI) | 52597 | 1-(2-oxiranyl)-1-ethanol | C4H8O2 | 详情 | 详情 | |
| (VII) | 54292 | 1-[(2R)oxiranyl]-1-ethanone | n/a | C4H6O2 | 详情 | 详情 |
| (VIII) | 52575 | 5-bromo-2-methyl-1-pentene | C6H11Br | 详情 | 详情 | |
| (IX) | 51602 | 1-Propyne | C3H4 | 详情 | 详情 | |
| (X) | 54295 | (1E,3S,5Z)-2,6,10-trimethyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5,10-undecatrien-3-ol | n/a | C18H27NOS | 详情 | 详情 |
| (XI) | 54296 | 2-methyl-4-{(1E,3S,5Z)-2,6,10-trimethyl-3-[(trimethylsilyl)oxy]-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 trimethylsilyl ether | n/a | C21H35NOSSi | 详情 | 详情 |
| (XII) | 54297 | (2S,6Z,9S,10E)-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-9-[(trimethylsilyl)oxy]-6,10-undecadienal | n/a | C21H35NO2SSi | 详情 | 详情 |
| (XIII) | 52596 | 3-hydroxy-4,4-dimethyl-5-oxoheptanoic acid | C9H16O4 | 详情 | 详情 | |
| (XIV) | 54298 | (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-trihydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid | n/a | C27H43NO6S | 详情 | 详情 |
| (XV) | 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：(XIII)The condensation of 3-buten-2-one (I) with the phosphonate (II) by means of LDA gives the alkylated thiazole (III), which is enantioselectively epoxidated to the chiral oxirane (V) by means of oxone and the chiral ketone (IV). Alternatively, the oxidation of the chiral epoxybutanol (VI) with CrO3 or SO3 /pyridine yields the epoxybutanone (VII), which is condensed with phosphorane (II) by means of LDA to afford the already reported chiral oxirane (V). The condensation of (V) with alkyl bromide (VIII) and propyne (IX) by means of Mg, CuBr and pentynyl lithium provides the undecatrienyl thiazole (X), which is treated with Tms-OTf in order to protect its OH group, yielding the silyl ether (XI). The oxidation of the terminal double bond of (XI) by means of (Ipc)2BH and CrO3 affords the carbaldehyde (XII), which is condensed with ketoacid (XIII) by means of LDA in THF to provide the undecadienoic acid (XIV). Finally, the cyclization of (XIV) by means of benzenesulfonyl chloride and pyridine gives 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 |
|---|---|---|---|---|---|---|
| 54294 | 1-pentynyllithium | n/a | C5H7Li | 详情 | 详情 | |
| (I) | 30324 | 3-buten-2-one; methyl vinyl ketone | 78-94-4 | C4H6O | 详情 | 详情 |
| (II) | 44442 | diethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate | C9H16NO3PS | 详情 | 详情 | |
| (III) | 54290 | 2-methyl-4-[(1E)-2-methyl-1,3-butadienyl]-1,3-thiazole | n/a | C9H11NS | 详情 | 详情 |
| (IV) | 54291 | n/a | C13H20O5 | 详情 | 详情 | |
| (V) | 54293 | 2-methyl-4-{(E)-2-[(2R)oxiranyl]-1-propenyl}-1,3-thiazole | n/a | C9H11NOS | 详情 | 详情 |
| (VI) | 52597 | 1-(2-oxiranyl)-1-ethanol | C4H8O2 | 详情 | 详情 | |
| (VII) | 54292 | 1-[(2R)oxiranyl]-1-ethanone | n/a | C4H6O2 | 详情 | 详情 |
| (VIII) | 52575 | 5-bromo-2-methyl-1-pentene | C6H11Br | 详情 | 详情 | |
| (IX) | 51602 | 1-Propyne | C3H4 | 详情 | 详情 | |
| (X) | 54295 | (1E,3S,5Z)-2,6,10-trimethyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5,10-undecatrien-3-ol | n/a | C18H27NOS | 详情 | 详情 |
| (XI) | 54296 | 2-methyl-4-{(1E,3S,5Z)-2,6,10-trimethyl-3-[(trimethylsilyl)oxy]-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 trimethylsilyl ether | n/a | C21H35NOSSi | 详情 | 详情 |
| (XII) | 54297 | (2S,6Z,9S,10E)-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-9-[(trimethylsilyl)oxy]-6,10-undecadienal | n/a | C21H35NO2SSi | 详情 | 详情 |
| (XIII) | 52596 | 3-hydroxy-4,4-dimethyl-5-oxoheptanoic acid | C9H16O4 | 详情 | 详情 | |
| (XIV) | 54298 | (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-trihydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid | n/a | C27H43NO6S | 详情 | 详情 |