【结 构 式】 |
【分子编号】58325 【品名】methyl (3S)-3-(1H-indol-3-yl)butanoate 【CA登记号】 |
【 分 子 式 】C13H15NO2 【 分 子 量 】217.26764 【元素组成】C 71.87% H 6.96% N 6.45% O 14.73% |
合成路线1
该中间体在本合成路线中的序号:(VIII)The reaction of indole-3-carbaldehyde (I) with benzyl chloroformate and NaH in THF gives the carbamate (II), which is condensed with the chiral oxazepinedione (III) by means of TiCl4 and pyridine in THF to yield a mixture of the cis (IV) and trans (V) adducts, which are easily separated by chromatography. The cis (IV) isomer can be thermally isomerized to the desired trans (V) isomer. The diastereoselective methylation of the double bond of (V) by means of MeMgBr in THF affords the methylated adduct (VI), which is hydrolyzed in acidic medium to afford the chiral indolylbutyric acid (VII). The reaction of (VII) with diazomethane provides the corresponding methyl ester (VIII), which is submitted to alpha hydroxylation by means of LDA, O2 and triethyl phosphite in HMPT/THF to give the chiral 2-hydroxy-3-(3-indolyl)butyric acid (IX). The protection of (IX) by means of dihydropyran (DHP) and Ts-OH yields the tetrahydropyranyl diprotected compound (X), which is hydrolyzed with LiOH in THF/water to afford the carboxylic acid (XI). The condensation of (XI) with N-methyl-thiourea (XII) by means of 2-chloro-3-ethylbenzoxazolium tetrafluoroborate (CEBF) and TEA in HMPT/dichloromethane provides a mixture of the S-acylisothiourea (XIII) and N-acylthiourea (XIV), which are easily separated. The S-acyl isomer (XIII) can be rearranged to the desired N-acyl isomer (XIV) by heating in refluxing dioxane. The N-acyl isomer (XIV) is deprotected by means of Ac-OH in THF/water to give the hydroxy derivative (XV), which is finally cyclized by means of CEBF and TEA in acetonitrile to afford the target indolmycin.
【1】 Takeda, T.; Mukaiyama, T.; Asymmetric total synthesis of indolmycin. Chem Lett 1980, 163. |
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) | 46797 | Indole-3-aldehyde; 3-Formylindole; 1H-Indole-3-carbaldehyde; Indole-3-carboxaldehyde | 487-89-8 | C9H7NO | 详情 | 详情 |
(II) | 58319 | benzyl 3-formyl-1H-indole-1-carboxylate | C17H13NO3 | 详情 | 详情 | |
(III) | 58320 | (2R,3S)-3,4-dimethyl-2-phenyl-1,4-oxazepane-5,7-dione | C13H15NO3 | 详情 | 详情 | |
(IV) | 58321 | benzyl 3-{[(2R,3S)-3,4-dimethyl-5,7-dioxo-2-phenyl-1,4-oxazepan-6-ylidene]methyl}-1H-indole-1-carboxylate | C30H26N2O5 | 详情 | 详情 | |
(V) | 58323 | benzyl 3-{[(2R,3S)-3,4-dimethyl-5,7-dioxo-2-phenyl-1,4-oxazepan-6-ylidene]methyl}-1H-indole-1-carboxylate | C30H26N2O5 | 详情 | 详情 | |
(VI) | 58322 | benzyl 3-{(1S)-1-[(2R,3S)-3,4-dimethyl-5,7-dioxo-2-phenyl-1,4-oxazepan-6-yl]ethyl}-1H-indole-1-carboxylate | C31H30N2O5 | 详情 | 详情 | |
(VII) | 58324 | (3S)-3-(1H-indol-3-yl)butanoic acid | C12H13NO2 | 详情 | 详情 | |
(VIII) | 58325 | methyl (3S)-3-(1H-indol-3-yl)butanoate | C13H15NO2 | 详情 | 详情 | |
(IX) | 58326 | methyl (2S,3R)-2-hydroxy-3-(1H-indol-3-yl)butanoate | C13H15NO3 | 详情 | 详情 | |
(X) | 58327 | methyl (2S,3R)-3-(1-tetrahydro-2H-pyran-2-yl-1H-indol-3-yl)-2-(tetrahydro-2H-pyran-2-yloxy)butanoate | C23H31NO5 | 详情 | 详情 | |
(XI) | 58328 | (2S,3R)-3-(1-tetrahydro-2H-pyran-2-yl-1H-indol-3-yl)-2-(tetrahydro-2H-pyran-2-yloxy)butanoic acid | C22H29NO5 | 详情 | 详情 | |
(XII) | 17283 | N-methylthiourea | 598-52-7 | C2H6N2S | 详情 | 详情 |
(XIII) | 58329 | S-[imino(methylamino)methyl] (2S,3R)-3-(1-tetrahydro-2H-pyran-2-yl-1H-indol-3-yl)-2-(tetrahydro-2H-pyran-2-yloxy)butanethioate | C24H33N3O4S | 详情 | 详情 | |
(XIV) | 58330 | N-methyl-N'-[(2S,3R)-3-(1-tetrahydro-2H-pyran-2-yl-1H-indol-3-yl)-2-(tetrahydro-2H-pyran-2-yloxy)butanoyl]thiourea | C24H33N3O4S | 详情 | 详情 | |
(XV) | 58331 | N-[(2S,3R)-2-hydroxy-3-(1H-indol-3-yl)butanoyl]-N'-methylthiourea | C14H17N3O2S | 详情 | 详情 |