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【结 构 式】 
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【分子编号】49287 【品名】(2R)-3-buten-2-ol 【CA登记号】33447-72-2 |
【 分 子 式 】C4H8O 【 分 子 量 】72.10692 【元素组成】C 66.63% H 11.18% O 22.19% |
合成路线1
该中间体在本合成路线中的序号：(II)The cyclization of phosphonate (I) with the chiral alcohol (II) by means of tert-butyl hypochlorite and Et-MgBr gives the isoxazoline (III), which is condensed with 2-methylthiazole-4-carbaldehyde (IV) by means of DBU and LiCl in acetonitrile to yield the secondary alcohol (V). The oxidation of (V) with TPAP and NMO in dichloromethane affords the corresponding ketone (VI), which is treated with the Grignard reagent (VII) in THF to provide the expected secondary alcohol (VIII). The silylation of (VIII) with Tes-OTf in dichloromethane gives the silyl ether (IX), which is treated with SmI2, Et3B and NaBH4 to cleave the isoxazoline ring and yield the diol (X). The reaction of (X) with SOCl2, TEA and TBAF affords the chiral epoxide (XI), which is silylated with Tes-Cl and TEA to provide the silyl ether (XII). The selective hydrolysis of the primary silyl ether of (XII) with HOAc in THF/water gives the primary alcohol (XIII), which is oxidized with TPAP and NMO in dichloromethane to yield the corresponding aldehyde (XIV). The condensation of (XIV) with ketone (XV) by means of LDA affords the open-chain precursor (XVI).
| 【1】 Bode, J.W.; Carreira, E.M.; Stereoselective syntheses of epothilones A and B via directed nitrile oxide cycloaddition. J Am Chem Soc 2001, 123, 18, 3611. |
| 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) | 49286 | diethyl 2-(hydroxyimino)-1-methylethylphosphonate | C7H16NO4P | 详情 | 详情 | |
| (II) | 49287 | (2R)-3-buten-2-ol | 33447-72-2 | C4H8O | 详情 | 详情 |
| (III) | 49288 | diethyl 1-[(5R)-5-[(1R)-1-hydroxyethyl]-4,5-dihydro-3-isoxazolyl]ethylphosphonate | C11H22NO5P | 详情 | 详情 | |
| (IV) | 44455 | 2-methyl-1,3-thiazole-4-carbaldehyde | C5H5NOS | 详情 | 详情 | |
| (V) | 49289 | (1R)-1-[(5R)-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydro-5-isoxazolyl]-1-ethanol | C12H16N2O2S | 详情 | 详情 | |
| (VI) | 49290 | 1-[(5R)-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydro-5-isoxazolyl]-1-ethanone | C12H14N2O2S | 详情 | 详情 | |
| (VII) | 49291 | bromo[(4S)-4-methyl-5-[(triisopropylsilyl)oxy]pentyl]magnesium | C15H33BrMgOSi | 详情 | 详情 | |
| (VIII) | 49292 | (2R,6S)-6-methyl-2-[(5R)-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydro-5-isoxazolyl]-7-[(triisopropylsilyl)oxy]-2-heptanol | C27H48N2O3SSi | 详情 | 详情 | |
| (IX) | 49293 | (5R)-5-[(1R,5S)-1,5-dimethyl-1-[(triethylsilyl)oxy]-6-[(triisopropylsilyl)oxy]hexyl]-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydroisoxazole; (1R,5S)-1,5-dimethyl-1-[(5R)-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydro-5-isoxazolyl]-6-[(triisopropylsilyl)oxy]hexyl triethylsilyl ether | C33H62N2O3SSi2 | 详情 | 详情 | |
| (X) | 49294 | (E,3S,5R,6R,10S)-2,6,10-trimethyl-1-(2-methyl-1,3-thiazol-4-yl)-6-[(triethylsilyl)oxy]-11-[(triisopropylsilyl)oxy]-1-undecene-3,5-diol | C33H65NO4SSi2 | 详情 | 详情 | |
| (XI) | 49295 | (2S,3E)-3-methyl-1-((2S,3R)-3-methyl-3-[(4S)-4-methyl-5-[(triisopropylsilyl)oxy]pentyl]oxiranyl)-4-(2-methyl-1,3-thiazol-4-yl)-3-buten-2-ol | C27H49NO3SSi | 详情 | 详情 | |
| (XII) | 49296 | (2S)-2-methyl-5-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)pentyl triisopropylsilyl ether; 2-methyl-4-[(E,3S)-2-methyl-4-((2S,3R)-3-methyl-3-[(4S)-4-methyl-5-[(triisopropylsilyl)oxy]pentyl]oxiranyl)-3-[(triethylsilyl)oxy]-1-butenyl]-1,3-thiazole | C33H63NO3SSi2 | 详情 | 详情 | |
| (XIII) | 49297 | (2S)-2-methyl-5-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)-1-pentanol | C24H43NO3SSi | 详情 | 详情 | |
| (XIV) | 49278 | (2S)-2-methyl-5-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)pentanal | C24H41NO3SSi | 详情 | 详情 | |
| (XV) | 44451 | (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one | C16H32O2Si | 详情 | 详情 | |
| (XVI) | 49298 | (4S,7R,8S,9S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-5,5,7,9-tetramethyl-12-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)-1-dodecen-6-one | C40H73NO5SSi2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The reaction of the oxime (I) with the 1-methylallyl alcohol (II) by means of Et-MgBr gives the isoxazoline (III), which is condensed with 2-methylthiazole-4-carbaldehyde (IV) by means of DBU and LiCl in acetonitrile to yield the adduct (V). The oxidation of (V) with TPAP and NMO affords the methyl ketone (VI), which is condensed with the Grignard reagent (VII) in THF to provide the tertiary alcohol (VIII). The protection of (VIII) by means of Tes-OTf gives the silylated compound (IX), which is oxidated with SmI2 in THF to yield the beta-hydroxy ketone (X). The reduction of (X) with Et3B and NaBH4 in THF/methanol affords the beta-diol (XI), which is treated with SOCl2, TEA and TBAF to provide the epoxide derivative (XII). The silylation of both OH groups of (XII) by means of Tes-Cl and TEA in dichloromethane furnishes the bis-silyl ether (XIII), which is selectively monodesilylated by means of AcOH in THF/water to give the primary alcohol (XIV). The oxidation of this alcohol by means of TPAP and NMO yields the carbaldehyde (XV).
| 【1】 Bode, J.W.; Carreira, E.M.; Stereoselective syntheses of epothilones A and B via nitrile oxide cycloadditions and related studies. J Org Chem 2001, 66, 19, 6410. |
| 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) | 60651 | dipropyl (1S)-2-chloro-2-(hydroxyimino)-1-methylethylphosphonate | C9H19ClNO4P | 详情 | 详情 | |
| (II) | 49287 | (2R)-3-buten-2-ol | 33447-72-2 | C4H8O | 详情 | 详情 |
| (III) | 60652 | diethyl (1S)-1-{(5R)-5-[(1R)-1-hydroxyethyl]-4,5-dihydro-3-isoxazolyl}ethylphosphonate | C11H22NO5P | 详情 | 详情 | |
| (IV) | 44455 | 2-methyl-1,3-thiazole-4-carbaldehyde | C5H5NOS | 详情 | 详情 | |
| (V) | 49289 | (1R)-1-[(5R)-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydro-5-isoxazolyl]-1-ethanol | C12H16N2O2S | 详情 | 详情 | |
| (VI) | 49290 | 1-[(5R)-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydro-5-isoxazolyl]-1-ethanone | C12H14N2O2S | 详情 | 详情 | |
| (VII) | 49291 | bromo[(4S)-4-methyl-5-[(triisopropylsilyl)oxy]pentyl]magnesium | C15H33BrMgOSi | 详情 | 详情 | |
| (VIII) | 49292 | (2R,6S)-6-methyl-2-[(5R)-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydro-5-isoxazolyl]-7-[(triisopropylsilyl)oxy]-2-heptanol | C27H48N2O3SSi | 详情 | 详情 | |
| (IX) | 49293 | (5R)-5-[(1R,5S)-1,5-dimethyl-1-[(triethylsilyl)oxy]-6-[(triisopropylsilyl)oxy]hexyl]-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydroisoxazole; (1R,5S)-1,5-dimethyl-1-[(5R)-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydro-5-isoxazolyl]-6-[(triisopropylsilyl)oxy]hexyl triethylsilyl ether | C33H62N2O3SSi2 | 详情 | 详情 | |
| (X) | 60653 | (E,5R,6R,10S)-5-hydroxy-2,6,10-trimethyl-1-(2-methyl-1,3-thiazol-4-yl)-6-[(triethylsilyl)oxy]-11-[(triisopropylsilyl)oxy]-1-undecen-3-one | C33H63NO4SSi2 | 详情 | 详情 | |
| (XI) | 49294 | (E,3S,5R,6R,10S)-2,6,10-trimethyl-1-(2-methyl-1,3-thiazol-4-yl)-6-[(triethylsilyl)oxy]-11-[(triisopropylsilyl)oxy]-1-undecene-3,5-diol | C33H65NO4SSi2 | 详情 | 详情 | |
| (XII) | 60654 | (2S,3E)-1-{(2S,3R)-3-[(4S)-5-hydroxy-4-methylpentyl]-3-methyloxiranyl}-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-buten-2-ol | C18H29NO3S | 详情 | 详情 | |
| (XIII) | 60655 | (2S)-2-methyl-5-((2R,3S)-2-methyl-3-{(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl}oxiranyl)pentyl triethylsilyl ether; 2-methyl-4-{(E,3S)-2-methyl-4-((2S,3R)-3-methyl-3-{(4S)-4-methyl-5-[(triethylsilyl)oxy]pentyl}oxiranyl)-3-[(triethylsilyl)oxy]-1-butenyl}-1,3-thiazole | C30H57NO3SSi2 | 详情 | 详情 | |
| (XIV) | 49297 | (2S)-2-methyl-5-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)-1-pentanol | C24H43NO3SSi | 详情 | 详情 | |
| (XV) | 49278 | (2S)-2-methyl-5-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)pentanal | C24H41NO3SSi | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)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4
该中间体在本合成路线中的序号：(I)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. |