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【结 构 式】 
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【分子编号】47401 【品名】allyl 3-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-2-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)phenylcarbamate 【CA登记号】 |
【 分 子 式 】C34H45NO6Si 【 分 子 量 】591.81994 【元素组成】C 69% H 7.66% N 2.37% O 16.22% Si 4.75% |
合成路线1
该中间体在本合成路线中的序号：(XXXIII)Synthesis of the aromatic intermediate (XXXIII): The esterification of the 5-hydroxyisophthalic acid (XVII) with SOCl2 and methanol gives the dimethyl ester (XVIII), which is treated with allyl bromide (XIX) and K2CO3 in refluxing acetone to yield the allyl ether (XX). The thermal isomerization of (XX) affords 4-allyl-5-hydroxyisophthalic acid dimethyl ester (XXI), which is treated with Bn-Br and K2CO3 in refluxing acetone to provide the benzyl ether (XXII). The hydrolysis of the ester groups of (XXII) with NaOH in THF gives the isophthalic acid (XXIII), which by reaction with Br2 and NaHCO3 yields the lactone (XXIV). The reduction of the carboxyl group of (XXIV) with isopropyl chloroformate and NaBH4 in THF/water affords the carbinol (XXV), which is protected with Bom-Cl and DIEA, providing compound (XXVI). The debromination of (XXVI) with Zn and NH4Cl in ethanol/water gives the 2-allylbenzoic acid (XXVII), which by a Curtius rearrangement with DPPA and TEA in refluxing tert-butanol yields the aryl carbamate (XXVIII). The reaction of (XXVIII) with OsO4 and NaIO4 in dioxane/water affords the indoline derivative (XXIX), which is treated with NaBH4 in EtOH to afford the 2-phenylethanol derivative (XXX). The reaction of (XXX) with Tbdms-Cl, TEA and DMAP provides the silyl ether (XXXI), which is treated with Tbdms-OTf and pyridine to give the aniline derivative (XXXII). Finally, this amine is reprotected with Alloc-Cl and NaHCO3 to yield the desired intermediate (XXXIII).
| 【1】 Katoh, T.; Terashima, S.; Total synthesis of antitumor antibiotic FR900482. Yuki Gosei Kagaku Kyokaishi 1997, 55, 11, 946. |
| 【2】 Yoshino, T.; et al.; Total synthesis of an enantiomeric pair of FR900482. 2. Syntheses of the aromatic and the optically active aliphatic segments. Tetrahedron 1997, 53, 30, 10239. |
| 【3】 Yoshino, T.; et al.; Total synthesis of natural (+)-FR900482. 2. Efficient syntheses of the aromatic and the optically active aliphatic fragments. Tetrahedron Lett 1996, 37, 20, 3475. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVII) | 47387 | 5-hydroxyisophthalic acid | 618-83-7 | C8H6O5 | 详情 | 详情 |
| (XVIII) | 31197 | dimethyl 5-hydroxyisophthalate | 13036-02-7 | C10H10O5 | 详情 | 详情 |
| (XIX) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (XX) | 47388 | dimethyl 5-(allyloxy)isophthalate | C13H14O5 | 详情 | 详情 | |
| (XXI) | 47389 | dimethyl 4-allyl-5-hydroxyisophthalate | C13H14O5 | 详情 | 详情 | |
| (XXII) | 47390 | dimethyl 4-allyl-5-(benzyloxy)isophthalate | C20H20O5 | 详情 | 详情 | |
| (XXIII) | 47391 | 4-allyl-5-(benzyloxy)isophthalic acid | C18H16O5 | 详情 | 详情 | |
| (XXIV) | 47392 | 5-(benzyloxy)-3-(bromomethyl)-1-oxo-3,4-dihydro-1H-isochromene-7-carboxylic acid | C18H15BrO5 | 详情 | 详情 | |
| (XXV) | 47393 | 5-(benzyloxy)-3-(bromomethyl)-7-(hydroxymethyl)-3,4-dihydro-1H-isochromen-1-one | C18H17BrO4 | 详情 | 详情 | |
| (XXVI) | 47394 | 5-(benzyloxy)-7-[[(benzyloxy)methoxy]methyl]-3-(bromomethyl)-3,4-dihydro-1H-isochromen-1-one | C26H25BrO5 | 详情 | 详情 | |
| (XXVII) | 47395 | 2-allyl-3-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]benzoic acid | C26H26O5 | 详情 | 详情 | |
| (XXVIII) | 47396 | tert-butyl 2-allyl-3-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]phenylcarbamate | C30H35NO5 | 详情 | 详情 | |
| (XXIX) | 47397 | tert-butyl 4-(benzyloxy)-6-[[(benzyloxy)methoxy]methyl]-2-hydroxy-1-indolinecarboxylate | C29H33NO6 | 详情 | 详情 | |
| (XXX) | 47398 | tert-butyl 3-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-2-(2-hydroxyethyl)phenylcarbamate | C29H35NO6 | 详情 | 详情 | |
| (XXXI) | 47399 | tert-butyl 3-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-2-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)phenylcarbamate | C35H49NO6Si | 详情 | 详情 | |
| (XXXII) | 47400 | 3-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-2-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)phenylamine; 3-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-2-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)aniline | C30H41NO4Si | 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 |
合成路线2
该中间体在本合成路线中的序号：(XXXIII)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 |