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【结 构 式】 
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【分子编号】14989 【品名】(2R,3S,4R,7S,9S,10E)-2,3-dihydroxy-11-iodo-9-methoxy-4,10-dimethyl-7-[(triisopropylsilyl)oxy]-10-undecenoic acid 【CA登记号】 |
【 分 子 式 】C23H45IO6Si 【 分 子 量 】572.59667 【元素组成】C 48.25% H 7.92% I 22.16% O 16.77% Si 4.9% |
合成路线1
该中间体在本合成路线中的序号：(I)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：(I)The intermediates (I) and (II) are synthesized as follows: Intermediate (I): The carboxylic acid (VIII) is condensed with N-methoxy-N-methylamine by means of dicyclohexylcarbodiimide (DCC) in dichloromethane to the amide (IX), which is treated with the vinyl iodide (X) and butyllithium in ethyl ether to yield the ketone (XI). The reduction of (XI) with LiAlH4 followed by methylation with MeI and NaH in DMF affords the methoxy compound (XII), which by treatment with camphorsulfonic acid (CSA), triethylamine and K2CO3 in methanol is converted to the epoxide (XIII). The condensation of (XIII) with the iodo ether (XIV) by means of butyllithium followed by silylation with triisopropylsilyl trifluoromethanesulfonate in dichloromethane and iodination with N-iodosuccinimide (NIS) in THF gives the protected triol (XV), which is selectively oxidized with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and oxalyl chloride in DMSO/dichloromethane, yielding the aldehyde (XVI). The condensation of (XVI) with the oxazolidinone (XVII) by means of tributylboron trifluoromethanesulfonate in toluene/dichloromethane affords compound (XVIII), which is treated with LiOH and H2O2 in THF/water. The resulting free acid is methylated with diazomethane, and the free hydroxyl group is acetylated with acetic anhydride to the acetoxy ester (XIX). Finally, (XIX) is hydrolyzed with LiOH in methanol/water to afford intermediate (I) (see A.D. Piscopio et al., J Chem Soc Chem Commun 1993, 7: 617). (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 | |
| (VIII) | 14996 | 2-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]acetic acid | C7H12O4 | 详情 | 详情 | |
| (IX) | 14997 | 2-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-N-methoxy-N-methylacetamide | C9H17NO4 | 详情 | 详情 | |
| (X) | 14998 | [(E)-2-iodo-1-propenyl](trimethyl)silane | C6H13ISi | 详情 | 详情 | |
| (XI) | 14999 | (E)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-3-methyl-4-(trimethylsilyl)-3-buten-2-one | C13H24O3Si | 详情 | 详情 | |
| (XII) | 15000 | [(E,3S)-4-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-3-methoxy-2-methyl-1-butenyl](trimethyl)silane; (1S,2E)-1-[[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl]-2-methyl-3-(trimethylsilyl)-2-propenyl methyl ether | C14H28O3Si | 详情 | 详情 | |
| (XIII) | 15001 | methyl (1S,2E)-2-methyl-1-[(2R)oxiranylmethyl]-3-(trimethylsilyl)-2-propenyl ether; [(E,3S)-3-methoxy-2-methyl-4-[(2R)oxiranyl]-1-butenyl](trimethyl)silane | C11H22O2Si | 详情 | 详情 | |
| (XIV) | 15002 | (2S)-3-iodo-2-methylpropyl 4-methoxybenzyl ether; 1-([[(2S)-3-iodo-2-methylpropyl]oxy]methyl)-4-methoxybenzene | C12H17IO2 | 详情 | 详情 | |
| (XV) | 15003 | [((1S,3S,4E)-5-iodo-3-methoxy-1-[(3R)-4-[(4-methoxybenzyl)oxy]-3-methylbutyl]-4-methyl-4-pentenyl)oxy](triisopropyl)silane; (1S,2E)-3-iodo-1-[(2S,5R)-6-[(4-methoxybenzyl)oxy]-5-methyl-2-[(triisopropylsilyl)oxy]hexyl]-2-methyl-2-propenyl methyl ether | C29H51IO4Si | 详情 | 详情 | |
| (XVI) | 15004 | (2R,5S,7S,8E)-9-iodo-7-methoxy-2,8-dimethyl-5-[(triisopropylsilyl)oxy]-8-nonenal | C21H41IO3Si | 详情 | 详情 | |
| (XVII) | 15005 | (4R,5S)-3-[2-[(4-methoxybenzyl)oxy]acetyl]-4-methyl-5-phenyl-1,3-oxazolan-2-one | C20H21NO5 | 详情 | 详情 | |
| (XVIII) | 15006 | (4R,5S)-3-[(2R,3S,4R,7S,9S,10E)-3-hydroxy-11-iodo-9-methoxy-2-[(4-methoxybenzyl)oxy]-4,10-dimethyl-7-[(triisopropylsilyl)oxy]-10-undecenoyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one | C41H62INO8Si | 详情 | 详情 | |
| (XIX) | 15007 | methyl (2R,3S,4R,7S,9S,10E)-3-(acetoxy)-2-hydroxy-11-iodo-9-methoxy-4,10-dimethyl-7-[(triisopropylsilyl)oxy]-10-undecenoate | C26H49IO7Si | 详情 | 详情 |