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【结 构 式】 
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【分子编号】52597 【品名】1-(2-oxiranyl)-1-ethanol 【CA登记号】 |
【 分 子 式 】C4H8O2 【 分 子 量 】88.10632 【元素组成】C 54.53% H 9.15% O 36.32% |
合成路线1
该中间体在本合成路线中的序号：(VII)The silylation of the epoxide (VII) with Tbdms-Cl gives the silyl ether (VIII), which is condensed with alkynyl aluminum (X) (obtained by reaction of 5-(tert-butyldimethylsilyloxy)-1-pentyne (IX) with dimethylaluminum and BuLi) in toluene, followed by treatment with HOAc to yield the unsaturated diol (XI). The controlled hydrogenation of the triple bond of (XI) with H2 over Lindlar catalyst affords the (Z)-olefin (XII), which is treated with Ts-Cl to provide the monotosylate (XIII). The silylation of the remaining OH group of (XIII) with Tms-OTf gives the fully protected triol (XIV), which is treated with NaI in refluxing acetone to yield the iodide (XV). The condensation of (XV) with the chiral amide (XVI) by means of BuLi in THF/HMPA affords the adduct (XVII), which by elimination of the chiral auxiliary by reduction with DIBAL in dichloromethane, followed by controlled oxidation with SO3/pyridine, provides the aldehyde (XVIII). The aldol condensation of aldehyde (XVIII) with the intermediate oxoacid (VI) by means of LDA in THF gives the heptadecanoic acid (XIX), which is fully silylated with Tbdms-OTf and lutidine, yielding the silylated silyl ester (XX). Selective elimination of the Tms and ester-Tbdms- groups with aqueous HOAc affords the hydroxyacid (XXI).
| 【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 |
|---|---|---|---|---|---|---|
| (VI) | 43166 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid | C15H30O4Si | 详情 | 详情 | |
| (VII) | 52597 | 1-(2-oxiranyl)-1-ethanol | C4H8O2 | 详情 | 详情 | |
| (VIII) | 52598 | (1,1-dimethylethyl)(dimethyl)((1-(2-oxiranyl)ethyl)oxy)silane; (1,1-dimethylethyl)(dimethyl)silyl 1-(2-oxiranyl)ethyl ether | C10H22O2Si | 详情 | 详情 | |
| (IX) | 52599 | 4-pentynyl trimethylsilyl ether; trimethyl(4-pentynyloxy)silane | C8H16OSi | 详情 | 详情 | |
| (X) | 52600 | dimethyl{5-[(trimethylsilyl)oxy]-1-pentynyl}aluminium | C10H21AlOSi | 详情 | 详情 | |
| (XI) | 52601 | 8-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-4-nonyne-1,7-diol | C15H30O3Si | 详情 | 详情 | |
| (XII) | 52602 | 8-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-4-nonene-1,7-diol | C15H32O3Si | 详情 | 详情 | |
| (XIII) | 52603 | 8-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-7-hydroxy-4-nonenyl 4-methylbenzenesulfonate | C22H38O5SSi | 详情 | 详情 | |
| (XIV) | 52604 | 8-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-7-[(trimethylsilyl)oxy]-4-nonenyl 4-methylbenzenesulfonate | C25H46O5SSi2 | 详情 | 详情 | |
| (XV) | 52605 | 4-(6-iodo-2-hexenyl)-2,2,5,7,7,8,8-heptamethyl-3,6-dioxa-2,7-disilanonane; (1,1-dimethylethyl)(dimethyl)silyl 8-iodo-1-methyl-2-[(trimethylsilyl)oxy]-4-octenyl ether | C18H39IO2Si2 | 详情 | 详情 | |
| (XVI) | 52606 | C13H21NO3S | 详情 | 详情 | ||
| (XVII) | 52607 | C31H59NO5SSi2 | 详情 | 详情 | ||
| (XVIII) | 52608 | 10-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-methyl-9-[(trimethylsilyl)oxy]-6-undecenal | C21H44O3Si2 | 详情 | 详情 | |
| (XIX) | 52609 | 3,16-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-7-hydroxy-4,4,6,8-tetramethyl-5-oxo-15-[(trimethylsilyl)oxy]-12-heptadecenoic acid | C36H74O7Si3 | 详情 | 详情 | |
| (XX) | 52610 | (1,1-dimethylethyl)(dimethyl)silyl 3,7,16-tris{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-4,4,6,8-tetramethyl-5-oxo-15-[(trimethylsilyl)oxy]-12-heptadecenoate | C48H102O7Si5 | 详情 | 详情 | |
| (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 |
合成路线2
该中间体在本合成路线中的序号：(VI)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：(VI)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 |