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【结 构 式】 
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【分子编号】47386 【品名】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 【CA登记号】 |
【 分 子 式 】C27H33Cl3F3NO7SSi 【 分 子 量 】707.0663696 【元素组成】C 45.87% H 4.7% Cl 15.04% F 8.06% N 1.98% O 15.84% S 4.54% Si 3.97% |
合成路线1
该中间体在本合成路线中的序号：(XVI)Synthesis of oxazolidine intermediate (XVI): The reaction of dimethyl L-tartrate (I) with benzaldehyde and Ts-OH gives the benzylidene ketal (II), which is reduced with LiAlH4/AlCl3 to yield the monobenzylated tetrol (III). The reaction of (III) with 2,2-dimethoxypropane (IV) and TsOH affords the acetonide (V), which is protected at the primary OH group with Mpm-Cl and NaH to provide the corresponding ether (VI). The debenzylation of (VI) with H2 over Raney-Ni in ethanol, followed by reaction with MsCl and TEA in dichloromethane, gives the mesylate (VII), which is treated with HCl in methanol to yield the diol (VIII). The reaction of (VIII) with K2CO3 in methanol affords the epoxide (IX), which is opened with NaN3 in refluxing ethanol to provide the azide (X). The selective monosilylation of (X) with Tbdps-Cl, TEA and DMAP in dichloromethane furnishes the silyl ether (XI). The reduction of the azido group of (XI) with PPh3 in THF/water gives the amine (XII), which is protected with Troc-Cl and NaHCO3 to afford the carbamate (XIII). The reaction of (XIII) with 2,2-dimethoxypropane (IV) and TsOH provides the oxazolidine (XIV), which is selectively deprotected at the Mpm group with DDQ in dichloromethane, giving the primary alcohol (XV). Finally, this compound is esterified with Tf2O and TEA in CH2Cl2 to obtain the desired oxazolidine intermediate (XVI).
| 【1】 Al-Hakim, A.H.; et al.; Synthesis of 1,2-O-isopropylidene-L-threitol and its conversion to (R)-1,2-O-isopropylideneglycerol. Synthesis 1985, 207. |
| 【2】 Katoh, T.; Terashima, S.; Total synthesis of antitumor antibiotic FR900482. Yuki Gosei Kagaku Kyokaishi 1997, 55, 11, 946. |
| 【3】 Ohno, M.; et al.; An enantioselective synthesis of platelet-activating factors, their enantiomers, and their analogues from D- and L-tartaric acids. Chem Pharm Bull 1985, 33, 2, 572. |
| 【4】 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. |
| 【5】 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. |
| 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) | 28476 | dimethyl (2S,3S)-2,3-dimethylbutanedioate | C6H10O6 | 详情 | 详情 | |
| (II) | 47374 | dimethyl (4R,5R)-2-phenyl-1,3-dioxolane-4,5-dicarboxylate | 38270-72-3 | C13H14O6 | 详情 | 详情 |
| (III) | 43826 | (2S,3S)-3-(benzyloxy)-1,2,4-butanetriol | C11H16O4 | 详情 | 详情 | |
| (IV) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (V) | 47375 | (2S)-2-(benzyloxy)-2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-1-ethanol | C14H20O4 | 详情 | 详情 | |
| (VI) | 47376 | (4S)-4-[(1S)-1-(benzyloxy)-2-[(4-methoxybenzyl)oxy]ethyl]-2,2-dimethyl-1,3-dioxolane; benzyl (1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-[(4-methoxybenzyl)oxy]ethyl ether | C22H28O5 | 详情 | 详情 | |
| (VII) | 47377 | (1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-[(4-methoxybenzyl)oxy]ethyl methanesulfonate | C16H24O7S | 详情 | 详情 | |
| (VIII) | 47378 | (1S,2S)-2,3-dihydroxy-1-[[(4-methoxybenzyl)oxy]methyl]propyl methanesulfonate | C13H20O7S | 详情 | 详情 | |
| (IX) | 47379 | ((2S,3R)-3-[[(4-methoxybenzyl)oxy]methyl]oxiranyl)methanol | C12H16O4 | 详情 | 详情 | |
| (X) | 47380 | (2R,3S)-2-azido-4-[(4-methoxybenzyl)oxy]-1,3-butanediol | C12H17N3O4 | 详情 | 详情 | |
| (XI) | 47381 | (2S,3R)-3-azido-4-[[tert-butyl(diphenyl)silyl]oxy]-1-[(4-methoxybenzyl)oxy]-2-butanol | C28H35N3O4Si | 详情 | 详情 | |
| (XII) | 47382 | (2S,3R)-3-amino-4-[[tert-butyl(diphenyl)silyl]oxy]-1-[(4-methoxybenzyl)oxy]-2-butanol | C28H37NO4Si | 详情 | 详情 | |
| (XIII) | 47383 | 2,2,2-trichloroethyl (1R,2S)-1-([[tert-butyl(diphenyl)silyl]oxy]methyl)-2-hydroxy-3-[(4-methoxybenzyl)oxy]propylcarbamate | C31H38Cl3NO6Si | 详情 | 详情 | |
| (XIV) | 47384 | 2,2,2-trichloroethyl (4R)-4-([[tert-butyl(diphenyl)silyl]oxy]methyl)-5-[[(4-methoxybenzyl)oxy]methyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C34H42Cl3NO6Si | 详情 | 详情 | |
| (XV) | 47385 | 2,2,2-trichloroethyl (4R)-4-([[tert-butyl(diphenyl)silyl]oxy]methyl)-5-(hydroxymethyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C26H34Cl3NO5Si | 详情 | 详情 | |
| (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 |
合成路线2
该中间体在本合成路线中的序号：(XVI)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 |