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【结 构 式】 
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【分子编号】15009 【品名】(3S,4R,5E,7R,8S,9R,10R,12S)-8-methoxy-3,9-bis[(4-methoxybenzyl)oxy]-4,6,10,12-tetramethyl-7-[(triisopropylsilyl)oxy]-5,13-tetradecadienal 【CA登记号】 |
【 分 子 式 】C44H70O7Si 【 分 子 量 】739.1211 【元素组成】C 71.5% H 9.55% O 15.15% Si 3.8% |
合成路线1
该中间体在本合成路线中的序号：(XXI)Intermediate (II): Compound (II) is obtained starting from two new previously synthesized intermediates, the oxazolidinone (XX) (scheme 17565203d) and the aldehyde (XXI) (scheme 17565203e), which are condensed by means of dibutylboron trifluoromethanesulfonate in dichloromethane to give compound (XXII), which is reduced first with LiBH4, tosylated with tosyl chloride and reduced again with lithium triethylborohydride in THF to yield compound (XXIII). The esterification of (XXIII) with the piperidine-2-carboxylic acid (XXIV) by means of DIC in dichloromethane followed by iodination of the terminal vinyl group by means of OsO4-catalyzed diol formation - Pb(OAc)4 cleavage, followed by CrCl2-mediated iodo-olefination with triiodomethane in THF/dioxane, affords the iodovinyl ester (XXV). Finally, (XXV) is debenzylated with DDQ in CHCl3 and silylated with triethylsilyl trifluoromethanesulfonate in dichloromethane to afford intermediate (II) (see K.C. Nicolau et al., J Chem Soc Chem Commun 1993, 7: 619). (1,2)
| 【1】 Nicolaou, K.C.; Piscopio, A.D.; Bertinato, P.; Chakraborty, T.K.; Minowa, N.; Koide, K.; Total Synthesis of Rapamycin. Chemistry (Weinheim) 1995, 1, 5, 318. |
| 【2】 Nicolaou, K.C.; Chakraborty, T.K.; Piscopio, A.D.; Minowa, N.; Bertinato, P.; Total synthesis of rapamycin. J Am Chem Soc 1993, 115, 10, 4419. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 14990 | (1S,3S,4R,5E,7R,8R,9R,10R,12S,13E)-1-[(1R)-2-((1S,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-1-methylethyl]-14-iodo-8-methoxy-4,6,10,12-tetramethyl-3,9-bis(triethylsilyl)-7-[(triisopropylsilyl)oxy]-5,13-tetradecadienyl (2S)-2-piperidinecarboxylate | C72H128INO6Si4 | 详情 | 详情 | |
| (XX) | 15008 | (4R,5S)-3-[3-((1S,3R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)propanoyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one | C36H45NO5Si | 详情 | 详情 | |
| (XXI) | 15009 | (3S,4R,5E,7R,8S,9R,10R,12S)-8-methoxy-3,9-bis[(4-methoxybenzyl)oxy]-4,6,10,12-tetramethyl-7-[(triisopropylsilyl)oxy]-5,13-tetradecadienal | C44H70O7Si | 详情 | 详情 | |
| (XXII) | 15010 | (4R,5S)-3-[(2R,3S,5S,6R,7E,9R,10S,11R,12R,14S)-2-[((1S,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)methyl]-3-hydroxy-10-methoxy-5,11-bis[(4-methoxybenzyl)oxy]-6,8,12,14-tetramethyl-9-[(triisopropylsilyl)oxy]-7,15-hexadecadienoyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one | C80H115NO12Si2 | 详情 | 详情 | |
| (XXIII) | 15011 | (2R,3S,5S,6R,7E,9R,10S,11R,12R,14S)-1-((1S,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-10-methoxy-5,11-bis[(4-methoxybenzyl)oxy]-2,6,8,12,14-pentamethyl-9-[(triisopropylsilyl)oxy]-7,15-hexadecadien-3-ol | C70H108O9Si2 | 详情 | 详情 | |
| (XXIV) | 11487 | (2S)-1-(tert-Butoxycarbonyl)hexahydro-2-pyridinecarboxylic acid | C11H19NO4 | 详情 | 详情 | |
| (XXV) | 15013 | 1-(tert-butyl) 2-[(1S,3S,4R,5E,7R,8S,9R,10R,12S,13E)-1-[(1R)-2-((1S,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-1-methylethyl]-14-iodo-8-methoxy-3,9-bis[(4-methoxybenzyl)oxy]-4,6,10,12-tetramethyl-7-[(triisopropylsilyl)oxy]-5,13-tetradecadienyl] (2S)-1,2-piperidinedicarboxylate | C81H124INO12Si2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXI)Aldehyde (XXI): The condensation of oxazolidinone (XXXVII) with aldehyde (XXXVIII) by means of dibutylboron trifluoromethanesulfonate in dichloromethane gives compound (XXXIX), which is reduced with LiBH4, tosyl chloride and lithium triethylborohydride as before, yielding the alcohol (XL). The deprotection of (XL) with tetrabutylammonium fluoride in THF followed by formation of a dioxane ring with p-methoxybenzaldehyde diethyl acetal and CSA in dichloromethane affords compound (XLI), which is submitted to a reductive ring opening with diiosbutylaluminum hydride in dichloromethane, followed by an oxidation with oxalyl chloride in DMSO/dichloromethane, yielding the aldehyde (XLII). The condensation of (XLII) with the unsaturated iodo compound (XLIII) by means of CrCl2 in DMSO gives the hydroxy derivative (XLIV), which is finally silylated with triisopropylsilyl trifluoromethanesulfonate in dichloromethane, selectively desilylated with HF - pyridine and oxidized with oxalyl chloride in DMSO/dichloromethane to the intermediate aldehyde (XXI) (see K.C. Nicolau et al., J Chem Soc Chem Commun 1993, 7: 619). The intermediate (XLIII) is prepared by ozonolysis of the protected unsaturated diol (XLV), followed by reaction with dimethylsulfide and tetrabromomethane - triphenylphosphine to obtain an acetylenic intermediate, which is methylated with butyllithium and methyl iodide to the acetylene (XLVI). Finally, this compound is iodinated with iodine and (cyclopentadienyl)2ZrHCl in dichloromethane to the intermediate (XLIII) (see K.C. Nicolau et al., J Chem Soc Chem Commun 1993, 7: 619). (1,2)
| 【1】 Nicolaou, K.C.; Piscopio, A.D.; Bertinato, P.; Chakraborty, T.K.; Minowa, N.; Koide, K.; Total Synthesis of Rapamycin. Chemistry (Weinheim) 1995, 1, 5, 318. |
| 【2】 Nicolaou, K.C.; Chakraborty, T.K.; Piscopio, A.D.; Minowa, N.; Bertinato, P.; Total synthesis of rapamycin. J Am Chem Soc 1993, 115, 10, 4419. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXI) | 15009 | (3S,4R,5E,7R,8S,9R,10R,12S)-8-methoxy-3,9-bis[(4-methoxybenzyl)oxy]-4,6,10,12-tetramethyl-7-[(triisopropylsilyl)oxy]-5,13-tetradecadienal | C44H70O7Si | 详情 | 详情 | |
| (XXXVII) | 15025 | (4R,5S)-4-methyl-3-[(4S)-4-methyl-5-hexenoyl]-5-phenyl-1,3-oxazolan-2-one | C17H21NO3 | 详情 | 详情 | |
| (XXXVIII) | 15026 | (2R)-3-[[tert-butyl(diphenyl)silyl]oxy]-2-methoxypropanal | C20H26O3Si | 详情 | 详情 | |
| (XXXIX) | 15027 | (4R,5S)-3-[(2R,4S)-2-((1R,2R)-3-[[tert-butyl(diphenyl)silyl]oxy]-1-hydroxy-2-methoxypropyl)-4-methyl-5-hexenoyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one | C37H47NO6Si | 详情 | 详情 | |
| (XL) | 15028 | (2R,3R,4R,6S)-1-[[tert-butyl(diphenyl)silyl]oxy]-2-methoxy-4,6-dimethyl-7-octen-3-ol | C27H40O3Si | 详情 | 详情 | |
| (XLI) | 15029 | 4-[(4R,5R)-4-[(1R,3S)-1,3-dimethyl-4-pentenyl]-5-methoxy-1,3-dioxan-2-yl]phenyl methyl ether; (4R,5R)-4-[(1R,3S)-1,3-dimethyl-4-pentenyl]-5-methoxy-2-(4-methoxyphenyl)-1,3-dioxane | C19H28O4 | 详情 | 详情 | |
| (XLII) | 15030 | (2S,3R,4R,6S)-2-methoxy-3-(4-methoxybenzyl)-4,6-dimethyl-7-octenal | C19H28O3 | 详情 | 详情 | |
| (XLIII) | 15031 | tert-butyl(dimethyl)silyl (3S,4S,5E)-6-iodo-3-(4-methoxybenzyl)-4-methyl-5-heptenyl ether; tert-butyl[[(3S,4S,5E)-6-iodo-3-(4-methoxybenzyl)-4-methyl-5-heptenyl]oxy]dimethylsilane | C22H37IO2Si | 详情 | 详情 | |
| (XLIV) | 15032 | (3S,4S,5E,7R,8S,9R,10R,12S)-1-[[tert-butyl(dimethyl)silyl]oxy]-8-methoxy-3,9-bis(4-methoxybenzyl)-4,6,10,12-tetramethyl-5,13-tetradecadien-7-ol | C41H66O5Si | 详情 | 详情 | |
| (XLV) | 15033 | tert-butyl[[(3S,4R)-3-(4-methoxybenzyl)-4-methyl-5-hexenyl]oxy]dimethylsilane; tert-butyl(dimethyl)silyl (3S,4R)-3-(4-methoxybenzyl)-4-methyl-5-hexenyl ether | C21H36O2Si | 详情 | 详情 | |
| (XLVI) | 15034 | tert-butyl(dimethyl)silyl (3S,4S)-3-(4-methoxybenzyl)-4-methyl-5-heptynyl ether; tert-butyl[[(3S,4S)-3-(4-methoxybenzyl)-4-methyl-5-heptynyl]oxy]dimethylsilane | C22H36O2Si | 详情 | 详情 |