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【结 构 式】 
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【分子编号】49315 【品名】(2S)-2-methyl-5-((2R,3S)-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)-1-pentanol 【CA登记号】 |
【 分 子 式 】C23H41NO3SSi 【 分 子 量 】439.73498 【元素组成】C 62.82% H 9.4% N 3.19% O 10.92% S 7.29% Si 6.39% |
合成路线1
该中间体在本合成路线中的序号：(XV)The ozonolysis of the terminal double bond of (I) gives the aldehyde (II), which is condensed with the acetylenic alcohol (II) by means of Zn(OTf)2 in the presence of (+)-N-methylephedrine to yield the chiral acetylenic diol (IV). The reaction of (IV) with benzoyl chloride and TEA affords the monobenzoate (V), which is treated with K2CO3 and LiAlH4 to provide the chiral allyl alcohol derivative (VI). The cyclization of (VI) with the phosphonate (VII) by means of Et-MgBr in isopropanol/dichloromethane gives the isooxazoline (VIII), which is treated with Tbdms-OTf to yield the corresponding silyl ether (IX). The condensation of (IX) with 2-methylthiazole-4-carbaldehyde (X) by means of DBU and LiCl affords the isooxazoline derivative (XI), which is treated with SmI2, Et3B and NaBH4 to cleave the isoxazoline ring and yield the diol (XII). The reaction of (XII) with SOCl2, TEA and TBAF affords the chiral epoxide (XIII), which is silylated with Tes-Cl and TEA to provide the silyl ether (XIV). The selective hydrolysis of the primary silyl ether of (XIV) with HOAc in THF/water gives the primary alcohol (XV), which is oxidized with TPAP and NMO in dichloromethane to yield the corresponding aldehyde (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) | 49304 | triisopropyl[[(2S)-2-methyl-6-heptenyl]oxy]silane; (2S)-2-methyl-6-heptenyl triisopropylsilyl ether | C17H36OSi | 详情 | 详情 | |
| (II) | 49305 | (5S)-5-methyl-6-[(triisopropylsilyl)oxy]hexanal | C16H34O2Si | 详情 | 详情 | |
| (III) | 17922 | 2-methyl-3-butyn-2-ol; 3-Methyl butynol | 115-19-5 | C5H8O | 详情 | 详情 |
| (IV) | 49306 | (5R,9S)-2,9-dimethyl-10-[(triisopropylsilyl)oxy]-3-decyne-2,5-diol | C21H42O3Si | 详情 | 详情 | |
| (V) | 49307 | (1R)-4-hydroxy-4-methyl-1-[(4S)-4-methyl-5-[(triisopropylsilyl)oxy]pentyl]-2-pentynyl benzoate | C28H46O4Si | 详情 | 详情 | |
| (VI) | 49308 | (3R,7S)-7-methyl-8-[(triisopropylsilyl)oxy]-1-octen-3-ol | C18H38O2Si | 详情 | 详情 | |
| (VII) | 49286 | diethyl 2-(hydroxyimino)-1-methylethylphosphonate | C7H16NO4P | 详情 | 详情 | |
| (VIII) | 49309 | diethyl 1-((5R)-5-[(1R,5S)-1-hydroxy-5-methyl-6-[(triisopropylsilyl)oxy]hexyl]-4,5-dihydro-3-isoxazolyl)ethylphosphonate | C25H52NO6PSi | 详情 | 详情 | |
| (IX) | 44455 | 2-methyl-1,3-thiazole-4-carbaldehyde | C5H5NOS | 详情 | 详情 | |
| (X) | 49310 | diethyl 1-((5R)-5-[(1R,5S)-1-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-[(triisopropylsilyl)oxy]hexyl]-4,5-dihydro-3-isoxazolyl)ethylphosphonate | C31H66NO6PSi2 | 详情 | 详情 | |
| (XI) | 49311 | (5R)-5-[(1R,5S)-1-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-[(triisopropylsilyl)oxy]hexyl]-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydroisoxazole; tert-butyl(dimethyl)silyl (1R,5S)-5-methyl-1-[(5R)-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydro-5-isoxazolyl]-6-[(triisopropylsilyl)oxy]hexyl ether | C32H60N2O3SSi2 | 详情 | 详情 | |
| (XII) | 49312 | (E,3S,5R,6R,10S)-6-[[tert-butyl(dimethyl)silyl]oxy]-2,10-dimethyl-1-(2-methyl-1,3-thiazol-4-yl)-11-[(triisopropylsilyl)oxy]-1-undecene-3,5-diol | C32H63NO4SSi2 | 详情 | 详情 | |
| (XIII) | 49313 | (2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-1-((2S,3R)-3-[(4S)-4-methyl-5-[(triisopropylsilyl)oxy]pentyl]oxiranyl)-3-buten-2-ol | C26H47NO3SSi | 详情 | 详情 | |
| (XIV) | 49314 | (2S)-2-methyl-5-((2R,3S)-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-[(4S)-4-methyl-5-[(triisopropylsilyl)oxy]pentyl]oxiranyl)-3-[(triethylsilyl)oxy]-1-butenyl]-1,3-thiazole | C32H61NO3SSi2 | 详情 | 详情 | |
| (XV) | 49315 | (2S)-2-methyl-5-((2R,3S)-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)-1-pentanol | C23H41NO3SSi | 详情 | 详情 | |
| (XVI) | 49316 | (2S)-2-methyl-5-((2R,3S)-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)pentanal | C23H39NO3SSi | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIX)The protection of 2(S)-methyl-6-hepten-1-ol (I) with Tes-Cl gives the silyl ether (II), which is oxidized by known methods to yield the aldehyde (III). The condensation of (III) with the acetylenic alcohol (IV) by means of Zn(OTf)2 and TEA to afford the acetylenic diol (V), which is selectively monobenzoylated with benzoyl chloride and TEA, providing the benzoate (VI). Extrusion of acetone from (VI) by means of K2CO3 in refluxing toluene gives the chiral octyne derivative (VII), which is reduced and debenzoylated with LiAlH4 in ethyl ether to yield the unsaturated alcohol (VIII). The condensation of (VIII) with the phosphonate (IX) by means of Et-MgBr affords the isoxazoline (X), which is treated with Tbdms-OTf and DIEA to provide the silyl ether (XI). The condensation of the phosphonate (XI) with 2-methylthiazole-4-carbaldehyde (XII) gives the adduct (XIII), which is treated with SmI2 to open the isoxazoline ring and yield the beta-hydroxy ketone (XIV). The reduction of (XIV) by means of BEt3 and NaBH4 affords the beta-diol (XV), which is treated with SOCl2 and TEA to provide the cyclic sulfite (XVI). The treatment of (XVI) with TBAF in refluxing THF/water gives the chiral epoxide (XVII), which is silylated with Tes-Cl and TEA to yield the bis silyl ether (XVIII). The selective deprotection of the primary silyl ether of (XVIII) by means of Ac-OH in THF/water affords the primary alcohol (XIX).
| 【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) | 27184 | (2S)-2-methyl-6-hepten-1-ol | C8H16O | 详情 | 详情 | |
| (II) | 49304 | triisopropyl[[(2S)-2-methyl-6-heptenyl]oxy]silane; (2S)-2-methyl-6-heptenyl triisopropylsilyl ether | C17H36OSi | 详情 | 详情 | |
| (III) | 49305 | (5S)-5-methyl-6-[(triisopropylsilyl)oxy]hexanal | C16H34O2Si | 详情 | 详情 | |
| (IV) | 17922 | 2-methyl-3-butyn-2-ol; 3-Methyl butynol | 115-19-5 | C5H8O | 详情 | 详情 |
| (V) | 49306 | (5R,9S)-2,9-dimethyl-10-[(triisopropylsilyl)oxy]-3-decyne-2,5-diol | C21H42O3Si | 详情 | 详情 | |
| (VI) | 49307 | (1R)-4-hydroxy-4-methyl-1-[(4S)-4-methyl-5-[(triisopropylsilyl)oxy]pentyl]-2-pentynyl benzoate | C28H46O4Si | 详情 | 详情 | |
| (VII) | 60464 | (1R)-1-{(4S)-4-methyl-5-[(triisopropylsilyl)oxy]pentyl}-2-propynyl benzoate | C25H40O3Si | 详情 | 详情 | |
| (VIII) | 49308 | (3R,7S)-7-methyl-8-[(triisopropylsilyl)oxy]-1-octen-3-ol | C18H38O2Si | 详情 | 详情 | |
| (IX) | 60465 | C4H8ClNO4PT | 详情 | 详情 | ||
| (X) | 60466 | C22H45NO6PSiT | 详情 | 详情 | ||
| (XI) | 60467 | C28H59NO6PSi2T | 详情 | 详情 | ||
| (XII) | 44455 | 2-methyl-1,3-thiazole-4-carbaldehyde | C5H5NOS | 详情 | 详情 | |
| (XIII) | 49311 | (5R)-5-[(1R,5S)-1-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-[(triisopropylsilyl)oxy]hexyl]-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydroisoxazole; tert-butyl(dimethyl)silyl (1R,5S)-5-methyl-1-[(5R)-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydro-5-isoxazolyl]-6-[(triisopropylsilyl)oxy]hexyl ether | C32H60N2O3SSi2 | 详情 | 详情 | |
| (XIV) | 60468 | (E,5R,6R,10S)-6-{[tert-butyl(dimethyl)silyl]oxy}-5-hydroxy-2,10-dimethyl-1-(2-methyl-1,3-thiazol-4-yl)-11-[(triisopropylsilyl)oxy]-1-undecen-3-one | C32H61NO4SSi2 | 详情 | 详情 | |
| (XV) | 49312 | (E,3S,5R,6R,10S)-6-[[tert-butyl(dimethyl)silyl]oxy]-2,10-dimethyl-1-(2-methyl-1,3-thiazol-4-yl)-11-[(triisopropylsilyl)oxy]-1-undecene-3,5-diol | C32H63NO4SSi2 | 详情 | 详情 | |
| (XVI) | 60469 | (4R,6S)-4-{(1R,5S)-1-{[tert-butyl(dimethyl)silyl]oxy}-5-methyl-6-[(triisopropylsilyl)oxy]hexyl}-6-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-1,3,2lambda~4~-dioxathian-2-one | C32H61NO5S2Si2 | 详情 | 详情 | |
| (XVII) | 60470 | (2S,3E)-1-{(2S,3R)-3-[(4S)-5-hydroxy-4-methylpentyl]oxiranyl}-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-buten-2-ol | C17H27NO3S | 详情 | 详情 | |
| (XVIII) | 60471 | (2S)-2-methyl-5-((2R,3S)-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-{(4S)-4-methyl-5-[(triethylsilyl)oxy]pentyl}oxiranyl)-3-[(triethylsilyl)oxy]-1-butenyl}-1,3-thiazole | C29H55NO3SSi2 | 详情 | 详情 | |
| (XIX) | 49315 | (2S)-2-methyl-5-((2R,3S)-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)-1-pentanol | C23H41NO3SSi | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIX)The oxidation of (XIX) by means of TPAP and NMO gives the aldehyde (XX), which is condensed with the chiral ketone (XXI) by means of LDA in THF to yield the aldol (XXII). The protection of the OH group of (XXII) with Troc-Cl and pyridine affords the Troc-ester (XXIII). The oxidation of the terminal vinyl group of (XXIII) with OsO4, NMO and Pb(OAc)4 provides the aldehyde (XXIV), which is selectively monodesilylated by treatment with HF and pyridine at 0 C to give the alcohol (XXV). The oxidation of the aldehyde group of (XXV) with NaClO2 yields the hydroxyacid (XXVI), which is submitted to macrolactonization by means of 2,4,6-trichlrobenzoyl chloride, TEA and DMAP to afford the protected macrolactone (XXVII). The cleavage of the Troc- protecting group of (XXVII) by means of Zn and NH4Cl in methanol provides the silylated precursor (XXVIII), which is finally treated with HF and pyridine at 40 C to furnish the target Epothilone A.
| 【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 |
|---|---|---|---|---|---|---|
| (XIX) | 49315 | (2S)-2-methyl-5-((2R,3S)-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)-1-pentanol | C23H41NO3SSi | 详情 | 详情 | |
| (XX) | 49316 | (2S)-2-methyl-5-((2R,3S)-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)pentanal | C23H39NO3SSi | 详情 | 详情 | |
| (XXI) | 44451 | (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one | C16H32O2Si | 详情 | 详情 | |
| (XXII) | 49317 | (4S,7R,8S,9S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-5,5,7,9-tetramethyl-12-((2R,3S)-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)-1-dodecen-6-one | C39H71NO5SSi2 | 详情 | 详情 | |
| (XXIII) | 60472 | trityl (3S,4R,7S)-7-{[tert-butyl(dimethyl)silyl]oxy}-4,6,6-trimethyl-3-[(1S)-1-methyl-4-((2R,3S)-3-{(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl}oxiranyl)butyl]-5-oxo-9-decenoate | C60H87NO6SSi2 | 详情 | 详情 | |
| (XXIV) | 60473 | trityl (3S,4R,7S)-7-{[tert-butyl(dimethyl)silyl]oxy}-4,6,6-trimethyl-3-[(1S)-1-methyl-4-((2R,3S)-3-{(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl}oxiranyl)butyl]-5,9-dioxononanoate | C59H85NO7SSi2 | 详情 | 详情 | |
| (XXV) | 60474 | trityl (3S,4R,7S)-7-{[tert-butyl(dimethyl)silyl]oxy}-3-((1S)-4-{(2R,3S)-3-[(2S,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]oxiranyl}-1-methylbutyl)-4,6,6-trimethyl-5,9-dioxononanoate | C53H71NO7SSi | 详情 | 详情 | |
| (XXVI) | 60475 | (3S,6R,7S,8S)-3-{[tert-butyl(dimethyl)silyl]oxy}-11-{(2R,3S)-3-[(2S,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]oxiranyl}-4,4,6,8-tetramethyl-5-oxo-7-[2-oxo-2-(trityloxy)ethyl]undecanoic acid | C53H71NO8SSi | 详情 | 详情 | |
| (XXVII) | 60476 | trityl 2-{(1S,3S,7S,10R,11S,12S,16R)-7-{[tert-butyl(dimethyl)silyl]oxy}-8,8,10,12-tetramethyl-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadec-11-yl}acetate | C53H69NO7SSi | 详情 | 详情 | |
| (XXVIII) | 49322 | (1S,3S,7S,10R,11S,12S,16R)-7-[[tert-butyl(dimethyl)silyl]oxy]-11-hydroxy-8,8,10,12-tetramethyl-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione | C32H53NO6SSi | 详情 | 详情 |