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【结 构 式】 
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【分子编号】14990 【品名】(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 【CA登记号】 |
【 分 子 式 】C72H128INO6Si4 【 分 子 量 】1343.05793 【元素组成】C 64.39% H 9.61% I 9.45% N 1.04% O 7.15% Si 8.36% |
合成路线1
该中间体在本合成路线中的序号：(II)The total synthesis of rapamycin has been performed by initial condensation of two previously synthesized intermediates, the carboxylic acid (I) (scheme 17565203b) and the piperidine (II) (scheme 17565203c), by means of diisopropylcarbodiimide (DIC) and 1-hydroxybenzotriazole (HBT) in dichloromethane to the acylated piperidine (III). The two free hydroxyl groups of (III) are oxidized with oxalyl chloride in DMSO/dichloromethane to the triketone (IV), which is selectively deprotected with HF - pyridine in THF and oxidized again with oxalyl chloride to the hexacarbonyl compound (V). The full deprotection of (V) with HF in acetonitrile produces the simultaneous cyclization of the tetrahydropyran ring, yielding (VI), which is finally cyclized to rapamycin with the distannane (VII) by means of diisopropylethylamine (IEN) and palladium dichloride acetonitrile complex in DMF/THF. (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 |
|---|---|---|---|---|---|---|
| (I) | 14989 | (2R,3S,4R,7S,9S,10E)-2,3-dihydroxy-11-iodo-9-methoxy-4,10-dimethyl-7-[(triisopropylsilyl)oxy]-10-undecenoic acid | C23H45IO6Si | 详情 | 详情 | |
| (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 | |
| (III) | 14991 | (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)-1-[(2R,3S,4R,7S,9S,10E)-2,3-dihydroxy-11-iodo-9-methoxy-4,10-dimethyl-7-[(triisopropylsilyl)oxy]-10-undecenoyl]-2-piperidinecarboxylate | C95H171I2NO11Si5 | 详情 | 详情 | |
| (IV) | 14992 | (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)-1-[(4R,7S,9S,10E)-11-iodo-9-methoxy-4,10-dimethyl-2,3-dioxo-7-[(triisopropylsilyl)oxy]-10-undecenoyl]-2-piperidinecarboxylate | C95H167I2NO11Si5 | 详情 | 详情 | |
| (V) | 14993 | (1S,4R,5E,7R,8R,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-dioxo-7-[(triisopropylsilyl)oxy]-5,13-tetradecadienyl (2S)-1-[(4R,7S,9S,10E)-11-iodo-9-methoxy-4,10-dimethyl-2,3-dioxo-7-[(triisopropylsilyl)oxy]-10-undecenoyl]-2-piperidinecarboxylate | C83H135I2NO13Si3 | 详情 | 详情 | |
| (VI) | 14994 | (1S,4R,5E,7R,8R,10R,12S,13E)-1-[(1R)-2-((1S,3R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methoxycyclohexyl)-1-methylethyl]-14-iodo-8-methoxy-4,6,10,12-tetramethyl-3,9-dioxo-7-[(triisopropylsilyl)oxy]-5,13-tetradecadienyl (2S)-1-[(4R,7S,9S,10E)-11-iodo-9-methoxy-4,10-dimethyl-2,3-dioxo-7-[(triisopropylsilyl)oxy]-10-undecenoyl]-2-piperidinecarboxylate | C73H131I2NO13Si3 | 详情 | 详情 | |
| (VII) | 14995 | tributyl[(E)-2-(tributylstannyl)ethenyl]stannane | C26H56Sn2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)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 |