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【结 构 式】 
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【分子编号】47412 【品名】allyl (1aS,8R,9aS)-7-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-8-(hydroxymethyl)-1-[(4-methylphenyl)sulfonyl]-9-oxo-1,1a,2,8,9,9a-hexahydro-3H-azireno[2,3-c][1]benzazocine-3-carboxylate 【CA登记号】 |
【 分 子 式 】C39H40N2O9S 【 分 子 量 】712.82068 【元素组成】C 65.71% H 5.66% N 3.93% O 20.2% S 4.5% |
合成路线1
该中间体在本合成路线中的序号：(XLIV)Assembly of the target compound: The condensation of intermediates (XVI) and (XXXIII) by means of NaH in THF gives the adduct (XXXIV), which is treated with Zn/HOAc in THF, yielding the aminoalcohol (XXXV). The selective protection of the NH2 and OH groups of (XXXV) with TsCl/TEA and MsCl/TEA, respectively, affords the fully protected compound (XXXVI), which is treated with NaH and imidazole in refluxing THF to provide the aziridine derivative (XXXVII). The desilylation of (XXXVII) with HF and pyridine furnishes the diol (XXXVIII), which is oxidized with DMP in CH2Cl2 to give the dialdehyde (XXXIX). The cyclization of (XXXIX) by means of LiHMDS in THF, followed by reduction with NaBH4, yields the tricyclic diol (XL), which is selectively silylated at the primary OH group with Tbdps-Cl, TEA and DMAP in CH2Cl2 to afford the monosilylated compound (XLI). The oxidation of the secondary OH group of (XLI) with DMP provides the cyclic ketone (XLII), which is desilylated with HF and pyridine to give the (S)-hydroxymethyl compound (XLIII). The treatment of (XLIII) with DBU in THF yields a mixture of the starting (S)-isomer (XLIII) and the desired (R)-isomer (XLIV) that is resolved by chromatography.
| 【1】 Katoh, T.; Terashima, S.; Total synthesis of antitumor antibiotic FR900482. Yuki Gosei Kagaku Kyokaishi 1997, 55, 11, 946. |
| 【2】 Katoh, T.; et al.; Total synthesis of an enantiomeric pair of FR900482. 3. Completion of the synthesis by assembling the two segments. Tetrahedron 1997, 53, 30, 10253. |
| 【3】 Katoh, T.; et al.; Total synthesis of natural (+)-FR900482. 3. Completion of the synthesis. Tetrahedron Lett 1996, 37, 20, 3479. |
| 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) | 47386 | 2,2,2-trichloroethyl (4R)-4-([[tert-butyl(diphenyl)silyl]oxy]methyl)-2,2-dimethyl-5-([[(trifluoromethyl)sulfonyl]oxy]methyl)-1,3-oxazolidine-3-carboxylate | C27H33Cl3F3NO7SSi | 详情 | 详情 | |
| (XXXIII) | 47401 | allyl 3-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-2-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)phenylcarbamate | C34H45NO6Si | 详情 | 详情 | |
| (XXXIV) | 47402 | 2,2,2-trichloroethyl (4R,5R)-5-[[[(allyloxy)carbonyl]-3-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-2-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)anilino]methyl]-4-([[tert-butyl(diphenyl)silyl]oxy]methyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C60H77Cl3N2O10Si2 | 详情 | 详情 | |
| (XXXV) | 47403 | allyl (2R,3R)-3-amino-4-[[tert-butyl(diphenyl)silyl]oxy]-2-hydroxybutyl[3-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-2-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)phenyl]carbamate | C54H72N2O8Si2 | 详情 | 详情 | |
| (XXXVI) | 47404 | (1R,2R)-1-[[[(allyloxy)carbonyl]-3-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-2-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)anilino]methyl]-3-[[tert-butyl(diphenyl)silyl]oxy]-2-[[(4-methylphenyl)sulfonyl]amino]propyl methanesulfonate | C62H80N2O12S2Si2 | 详情 | 详情 | |
| (XXXVII) | 47405 | allyl 3-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-2-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)phenyl([(2S,3S)-3-([[tert-butyl(diphenyl)silyl]oxy]methyl)-1-[(4-methylphenyl)sulfonyl]aziridinyl]methyl)carbamate | C61H76N2O9SSi2 | 详情 | 详情 | |
| (XXXVIII) | 47406 | allyl 3-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-2-(2-hydroxyethyl)phenyl([(2S,3S)-3-(hydroxymethyl)-1-[(4-methylphenyl)sulfonyl]aziridinyl]methyl)carbamate | C39H44N2O9S | 详情 | 详情 | |
| (XXXIX) | 47407 | allyl 3-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-2-(2-oxoethyl)phenyl([(2S,3S)-3-formyl-1-[(4-methylphenyl)sulfonyl]aziridinyl]methyl)carbamate | C39H40N2O9S | 详情 | 详情 | |
| (XL) | 47408 | allyl (1aS,8S,9S,9aS)-7-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-9-hydroxy-8-(hydroxymethyl)-1-[(4-methylphenyl)sulfonyl]-1,1a,2,8,9,9a-hexahydro-3H-azireno[2,3-c][1]benzazocine-3-carboxylate | C39H42N2O9S | 详情 | 详情 | |
| (XLI) | 47409 | allyl (1aS,8S,9S,9aS)-7-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-8-([[tert-butyl(diphenyl)silyl]oxy]methyl)-9-hydroxy-1-[(4-methylphenyl)sulfonyl]-1,1a,2,8,9,9a-hexahydro-3H-azireno[2,3-c][1]benzazocine-3-carboxylate | C55H60N2O9SSi | 详情 | 详情 | |
| (XLII) | 47410 | allyl (1aS,8S,9aS)-7-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-8-([[tert-butyl(diphenyl)silyl]oxy]methyl)-1-[(4-methylphenyl)sulfonyl]-9-oxo-1,1a,2,8,9,9a-hexahydro-3H-azireno[2,3-c][1]benzazocine-3-carboxylate | C55H58N2O9SSi | 详情 | 详情 | |
| (XLIII) | 47411 | allyl (1aS,8S,9aS)-7-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-8-(hydroxymethyl)-1-[(4-methylphenyl)sulfonyl]-9-oxo-1,1a,2,8,9,9a-hexahydro-3H-azireno[2,3-c][1]benzazocine-3-carboxylate | C39H40N2O9S | 详情 | 详情 | |
| (XLIV) | 47412 | allyl (1aS,8R,9aS)-7-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-8-(hydroxymethyl)-1-[(4-methylphenyl)sulfonyl]-9-oxo-1,1a,2,8,9,9a-hexahydro-3H-azireno[2,3-c][1]benzazocine-3-carboxylate | C39H40N2O9S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XLIV)The reduction of the carbonyl group of (XLIV) with NaBH4 in THF gives the diol (XLV), which is selectively silylated at the primary OH group with Tbdps-Cl, TEA and DMAP, yielding silyl ether (XLVI). Elimination of the Alloc protecting group with Pd(PPh3)4, PPh3 in THF affords compound (XLVII), which is carefully oxidized at the NH group with MCPBA in dichloromethane, providing the hydroyamine (XLVIII). The reaction of (XLVIII) with Ac2O gives the acetate (XLIX), which is oxidized with DMP to yield the ketone (L). The desilylation of (L) with HF and pyridine affords the hydroxyketone (LI), which by treatment with K2CO3 in methanol undergoes cyclization to the tetracyclic compound (LIII) through the intermediate dihydroxyketone (LII). The reaction of (LIII) with diphosgene and pyridine gives the cyclic carbonate (LIV), which is treated with ammonia in THF, yielding the carbamic ester (LV).
| 【1】 Katoh, T.; Terashima, S.; Total synthesis of antitumor antibiotic FR900482. Yuki Gosei Kagaku Kyokaishi 1997, 55, 11, 946. |
| 【2】 Katoh, T.; et al.; Total synthesis of natural (+)-FR900482. 3. Completion of the synthesis. Tetrahedron Lett 1996, 37, 20, 3479. |
| 【3】 Katoh, T.; et al.; Total synthesis of an enantiomeric pair of FR900482. 3. Completion of the synthesis by assembling the two segments. Tetrahedron 1997, 53, 30, 10253. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XLIV) | 47412 | allyl (1aS,8R,9aS)-7-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-8-(hydroxymethyl)-1-[(4-methylphenyl)sulfonyl]-9-oxo-1,1a,2,8,9,9a-hexahydro-3H-azireno[2,3-c][1]benzazocine-3-carboxylate | C39H40N2O9S | 详情 | 详情 | |
| (XLV) | 47413 | allyl (1aS,8R,9R,9aS)-7-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-9-hydroxy-8-(hydroxymethyl)-1-[(4-methylphenyl)sulfonyl]-1,1a,2,8,9,9a-hexahydro-3H-azireno[2,3-c][1]benzazocine-3-carboxylate | C39H42N2O9S | 详情 | 详情 | |
| (XLVI) | 47414 | allyl (1aS,8R,9R,9aS)-7-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-8-([[tert-butyl(diphenyl)silyl]oxy]methyl)-9-hydroxy-1-[(4-methylphenyl)sulfonyl]-1,1a,2,8,9,9a-hexahydro-3H-azireno[2,3-c][1]benzazocine-3-carboxylate | C55H60N2O9SSi | 详情 | 详情 | |
| (XLVII) | 47415 | (1aS,8R,9R,9aS)-7-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-8-([[tert-butyl(diphenyl)silyl]oxy]methyl)-1-[(4-methylphenyl)sulfonyl]-1a,2,3,8,9,9a-hexahydro-1H-azireno[2,3-c][1]benzazocin-9-ol | C51H56N2O7SSi | 详情 | 详情 | |
| (XLVIII) | 47416 | (1aS,8R,9R,9aS)-7-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-8-([[tert-butyl(diphenyl)silyl]oxy]methyl)-1-[(4-methylphenyl)sulfonyl]-1,1a,2,8,9,9a-hexahydro-3H-azireno[2,3-c][1]benzazocine-3,9-diol | C51H56N2O8SSi | 详情 | 详情 | |
| (XLIX) | 47417 | (1aS,8R,9R,9aS)-3-(acetoxy)-7-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-8-([[tert-butyl(diphenyl)silyl]oxy]methyl)-1-[(4-methylphenyl)sulfonyl]-1a,2,3,8,9,9a-hexahydro-1H-azireno[2,3-c][1]benzazocin-9-ol | C53H58N2O9SSi | 详情 | 详情 | |
| (L) | 47418 | (1aS,8R,9aS)-3-(acetoxy)-7-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-8-([[tert-butyl(diphenyl)silyl]oxy]methyl)-1-[(4-methylphenyl)sulfonyl]-1,1a,2,3,8,9a-hexahydro-9H-azireno[2,3-c][1]benzazocin-9-one | C53H56N2O9SSi | 详情 | 详情 | |
| (LI) | 47419 | (1aS,8R,9aS)-3-(acetoxy)-7-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-8-(hydroxymethyl)-1-[(4-methylphenyl)sulfonyl]-1,1a,2,3,8,9a-hexahydro-9H-azireno[2,3-c][1]benzazocin-9-one | C37H38N2O9S | 详情 | 详情 | |
| (LII) | 47420 | (1aS,8R,9aS)-7-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-3-hydroxy-8-(hydroxymethyl)-1-[(4-methylphenyl)sulfonyl]-1,1a,2,3,8,9a-hexahydro-9H-azireno[2,3-c][1]benzazocin-9-one | C35H36N2O8S | 详情 | 详情 | |
| (LIII) | 47421 | (8R,9S,10S,12S)-6-(benzyloxy)-4-[[(benzyloxy)methoxy]methyl]-8-(hydroxymethyl)-11-[(4-methylphenyl)sulfonyl]-14-oxa-1,11-diazatetracyclo[7.4.1.0(2,7).0(10,12)]tetradeca-2,4,6-trien-9-ol | C35H36N2O8S | 详情 | 详情 | |
| (LIV) | 47422 | (1S,6R,15S,17S)-8-(benzyloxy)-10-[[(benzyloxy)methoxy]methyl]-16-[(4-methylphenyl)sulfonyl]-2,4,18-trioxa-13,16-diazapentacyclo[11.4.1.0(1,6).0(7,12).0(15,17)]octadeca-7,9,11-trien-3-one | C36H34N2O9S | 详情 | 详情 | |
| (LV) | 47423 | [(8R,9S,10S,12S)-6-(benzyloxy)-4-[[(benzyloxy)methoxy]methyl]-9-hydroxy-11-[(4-methylphenyl)sulfonyl]-14-oxa-1,11-diazatetracyclo[7.4.1.0(2,7).0(10,12)]tetradeca-2,4,6-trien-8-yl]methyl carbamate | C36H37N3O9S | 详情 | 详情 |