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【结 构 式】 
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【分子编号】49316 【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)pentanal 【CA登记号】 |
【 分 子 式 】C23H39NO3SSi 【 分 子 量 】437.7191 【元素组成】C 63.11% H 8.98% N 3.2% O 10.97% S 7.33% Si 6.42% |
合成路线1
该中间体在本合成路线中的序号：(XVI)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：(XVI)The condensation of (XVI) with ketone (XVII) by means of LDA affords the open-chain precursor (XVIII), which is protected at the OH group with Troc-Cl and pyridine to afford compound (XIX). The oxidation of (XIX) at the terminal vinyl group by means of OsO4, NMO and Pb(OAc)4 provides the carboxylic acid (XVIII), which by selective cleavage of its Tes- protecting group with HF and pyridine furnishes the hydroxyacid (XIX). The macrolactonization of (XIX) by means of 2,4,6-trichlorobenzoyl chloride gives the protected macrolactone (XX). The reaction of (XX) with Zn and NH4Cl in methanol cleaves the Troc-protecting group, yielding the silylated precursor (XXI), which is finally treated with HF and pyridine to afford the target epothilone A
| 【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 |
|---|---|---|---|---|---|---|
| (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 | |
| (XVII) | 44451 | (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one | C16H32O2Si | 详情 | 详情 | |
| (XVIII) | 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 | |
| (XIX) | 49318 | (1S,2R,5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4,4-trimethyl-1-[(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]-3-oxo-7-octenyl 2,2,2-trichloroethyl carbonate | C42H72Cl3NO7SSi2 | 详情 | 详情 | |
| (XX) | 49319 | (3S,6R,7S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-11-((2R,3S)-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)-5-oxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]undecanoic acid | C41H70Cl3NO9SSi2 | 详情 | 详情 | |
| (XXI) | 49320 | (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-[[(2,2,2-trichloroethoxy)carbonyl]oxy]undecanoic acid | C35H56Cl3NO9SSi | 详情 | 详情 | |
| (XXII) | 49321 | (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 2,2,2-trichloroethyl carbonate | C35H54Cl3NO8SSi | 详情 | 详情 | |
| (XXIII) | 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 |
合成路线3
该中间体在本合成路线中的序号：(XX)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 |