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【结 构 式】 
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【分子编号】35408 【品名】(E)-4-[2-[(1R,3R)-2-benzyl-6,8-diisopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-5-isopropoxyphenyl]-3-(ethoxycarbonyl)-3-butenoic acid 【CA登记号】 |
【 分 子 式 】C40H51NO7 【 分 子 量 】657.84748 【元素组成】C 73.03% H 7.81% N 2.13% O 17.02% |
合成路线1
该中间体在本合成路线中的序号：(X)2-Bromo-5-isopropoxybenzoic acid (I) was treated with oxalyl chloride to give the corresponding acid chloride (II) and subsequently condensed with the enantiomerically pure tetrahydroisoquinoline (III), yielding ester (IV). Intramolecular biaryl coupling by means of palladium acetate and tri(o-tolylphosphine) produced lactone (V), existing as an interconvertible mixture of its two atropo-diastereomeric forms. Reductive ring cleavage of this lactone using several hydride transfer reagents gave a separable mixture of two atropisomeric diols, from which the S-biar atropisomer (VI) was isolated by chromatography. After protection of the phenolic hydroxyl group of (VI) as the isopropyl ether (VII), oxidation of the primary alcohol with pyridinium chlorochromate (PCC) gave aldehyde (VIII). Stobbe condensation of (VIII) with diethyl succinate (IX) and NaOEt afforded the benzylidene succinic derivative (X).
| 【1】 Bringmann, G.; et al.; First atropo-divergent total synthesis of the antimalarial korupensamines A and B by the "lactone method". J Org Chem 2000, 65, 7, 2069. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 32658 | 2-bromopropane | 75-26-3 | C3H7Br | 详情 | 详情 | |
| (I) | 35400 | 2-bromo-4-isopropoxybenzoic acid | C10H11BrO3 | 详情 | 详情 | |
| (II) | 35401 | 2-bromo-4-isopropoxybenzoyl chloride | C10H10BrClO2 | 详情 | 详情 | |
| (III) | 35402 | (1R,3R)-2-benzyl-8-isopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-6-isoquinolinol | C21H27NO2 | 详情 | 详情 | |
| (IV) | 35403 | (1R,3R)-2-benzyl-8-isopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-6-isoquinolinyl 2-bromo-4-isopropoxybenzoate | C31H36BrNO4 | 详情 | 详情 | |
| (V) | 35404 | (2R,4R)-3-benzyl-5,10-diisopropoxy-2,4-dimethyl-1,2,3,4-tetrahydro-8H-isochromeno[4,3-f]isoquinolin-8-one | C31H35NO4 | 详情 | 详情 | |
| (VI) | 35405 | (1R,3R)-2-benzyl-5-[2-(hydroxymethyl)-4-isopropoxyphenyl]-8-isopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-6-isoquinolinol | C31H39NO4 | 详情 | 详情 | |
| (VII) | 35406 | [2-[(1R,3R)-2-benzyl-6,8-diisopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-5-isopropoxyphenyl]methanol | C34H45NO4 | 详情 | 详情 | |
| (VIII) | 35407 | 2-[(1R,3R)-2-benzyl-6,8-diisopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-5-isopropoxybenzaldehyde | C34H43NO4 | 详情 | 详情 | |
| (IX) | 12313 | diethyl succinate | 123-25-1 | C8H14O4 | 详情 | 详情 |
| (X) | 35408 | (E)-4-[2-[(1R,3R)-2-benzyl-6,8-diisopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-5-isopropoxyphenyl]-3-(ethoxycarbonyl)-3-butenoic acid | C40H51NO7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)Further intramolecular Friedel-Crafts acylation in boiling acetic anhydride gave rise to naphthalene (XI). Reduction of the ethyl ester group of (XI) with LiAlH4 also produced the reductive cleavage of the phenolic acetate to furnish diol (XII). Conversion of the hydroxymethyl group of (XII) into the required methyl group was achieved by chlorination upon treatment with dibromotetrachloroethane and triphenylphosphine, followed by reductive dehalogenation to the methyl analogue (XIII) with LiAlH4. The free hydroxyl group of (XIII) was then methylated with dimethyl sulfate using phase-transfer catalysis to provide methyl ether (XIV), which was treated with BCl3 in order to eliminate the isopropyl protecting groups yielding the trihydroxy derivative (XV). Finally, hydrogenolysis of the N-benzyl protecting group of (XV) over Pd/C yielded the title compound.
| 【1】 Bringmann, G.; et al.; First atropo-divergent total synthesis of the antimalarial korupensamines A and B by the "lactone method". J Org Chem 2000, 65, 7, 2069. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 35408 | (E)-4-[2-[(1R,3R)-2-benzyl-6,8-diisopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-5-isopropoxyphenyl]-3-(ethoxycarbonyl)-3-butenoic acid | C40H51NO7 | 详情 | 详情 | |
| (XI) | 35409 | ethyl 4-(acetoxy)-8-[(1R,3R)-2-benzyl-6,8-diisopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-5-isopropoxy-2-naphthoate | C42H51NO7 | 详情 | 详情 | |
| (XII) | 35410 | 5-[(1R,3R)-2-benzyl-6,8-diisopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-3-(hydroxymethyl)-8-isopropoxy-1-naphthol | C38H47NO5 | 详情 | 详情 | |
| (XIII) | 35411 | 5-[(1R,3R)-2-benzyl-6,8-diisopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-8-isopropoxy-3-methyl-1-naphthol | C38H47NO4 | 详情 | 详情 | |
| (XIV) | 35412 | 5-[(1R,3R)-2-benzyl-6,8-diisopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-8-isopropoxy-3-methyl-1-naphthyl methyl ether; (1R,3R)-2-benzyl-6,8-diisopropoxy-5-(4-isopropoxy-5-methoxy-7-methyl-1-naphthyl)-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline | C39H49NO4 | 详情 | 详情 | |
| (XV) | 35413 | (1R,3R)-2-benzyl-5-(4-hydroxy-5-methoxy-7-methyl-1-naphthyl)-1,3-dimethyl-1,2,3,4-tetrahydro-6,8-isoquinolinediol | C30H31NO4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(X)2-Bromo-5-isopropoxybenzoic acid (I) was treated with oxalyl chloride to give the corresponding acid chloride (II) and subsequently condensed with the enantiomerically pure tetrahydroisoquinoline (III), yielding ester (IV). Intramolecular biaryl coupling by means of palladium acetate and tri(o-tolylphosphine) produced lactone (V), existing as an interconvertible mixture of its two atropo-diastereomeric forms. Reductive ring cleavage of this lactone using several hydride transfer reagents gave a separable mixture of two atropisomeric diols, from which the R-biar atropisomer (VI) was isolated by chromatography. After protection of the phenolic hydroxyl group of (VI) as the isopropyl ether (VII), oxidation of the primary alcohol with pyridinium chlorochromate (PCC) gave aldehyde (VIII). Stobbe condensation of (VIII) with diethyl succinate (IX) and NaOEt afforded the benzylidene succinic derivative (X).
| 【1】 Bringmann, G.; et al.; First atropo-divergent total synthesis of the antimalarial korupensamines A and B by the "lactone method". J Org Chem 2000, 65, 7, 2069. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 32658 | 2-bromopropane | 75-26-3 | C3H7Br | 详情 | 详情 | |
| (I) | 35400 | 2-bromo-4-isopropoxybenzoic acid | C10H11BrO3 | 详情 | 详情 | |
| (II) | 35401 | 2-bromo-4-isopropoxybenzoyl chloride | C10H10BrClO2 | 详情 | 详情 | |
| (III) | 35402 | (1R,3R)-2-benzyl-8-isopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-6-isoquinolinol | C21H27NO2 | 详情 | 详情 | |
| (IV) | 35403 | (1R,3R)-2-benzyl-8-isopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-6-isoquinolinyl 2-bromo-4-isopropoxybenzoate | C31H36BrNO4 | 详情 | 详情 | |
| (V) | 35404 | (2R,4R)-3-benzyl-5,10-diisopropoxy-2,4-dimethyl-1,2,3,4-tetrahydro-8H-isochromeno[4,3-f]isoquinolin-8-one | C31H35NO4 | 详情 | 详情 | |
| (VI) | 35405 | (1R,3R)-2-benzyl-5-[2-(hydroxymethyl)-4-isopropoxyphenyl]-8-isopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-6-isoquinolinol | C31H39NO4 | 详情 | 详情 | |
| (VII) | 35406 | [2-[(1R,3R)-2-benzyl-6,8-diisopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-5-isopropoxyphenyl]methanol | C34H45NO4 | 详情 | 详情 | |
| (VIII) | 35407 | 2-[(1R,3R)-2-benzyl-6,8-diisopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-5-isopropoxybenzaldehyde | C34H43NO4 | 详情 | 详情 | |
| (IX) | 12313 | diethyl succinate | 123-25-1 | C8H14O4 | 详情 | 详情 |
| (X) | 35408 | (E)-4-[2-[(1R,3R)-2-benzyl-6,8-diisopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-5-isopropoxyphenyl]-3-(ethoxycarbonyl)-3-butenoic acid | C40H51NO7 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(X)Further intramolecular Friedel-Crafts acylation in boiling acetic anhydride gave rise to naphthalene (XI). Reduction of the ethyl ester group of (XI) with LiAlH4 also produced the reductive cleavage of the phenolic acetate to furnish diol (XII). Conversion of the hydroxymethyl group of (XII) into the required methyl group was achieved by chlorination upon treatment with dibromotetrachloroethane and triphenylphosphine, followed by reductive dehalogenation to the methyl analogue (XIII) with LiAlH4. The free hydroxyl group of (XIII) was then methylated with dimethyl sulfate using phase-transfer catalysis to provide methyl ether (XIV), which was treated with BCl3 in order to eliminate the isopropyl protecting groups yielding the trihydroxy derivative (XV). Finally, hydrogenolysis of the N-benzyl protecting group of (XV) over Pd/C yielded the title compound.
| 【1】 Bringmann, G.; et al.; First atropo-divergent total synthesis of the antimalarial korupensamines A and B by the "lactone method". J Org Chem 2000, 65, 7, 2069. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 35408 | (E)-4-[2-[(1R,3R)-2-benzyl-6,8-diisopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-5-isopropoxyphenyl]-3-(ethoxycarbonyl)-3-butenoic acid | C40H51NO7 | 详情 | 详情 | |
| (XI) | 35409 | ethyl 4-(acetoxy)-8-[(1R,3R)-2-benzyl-6,8-diisopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-5-isopropoxy-2-naphthoate | C42H51NO7 | 详情 | 详情 | |
| (XII) | 35410 | 5-[(1R,3R)-2-benzyl-6,8-diisopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-3-(hydroxymethyl)-8-isopropoxy-1-naphthol | C38H47NO5 | 详情 | 详情 | |
| (XIII) | 35411 | 5-[(1R,3R)-2-benzyl-6,8-diisopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-8-isopropoxy-3-methyl-1-naphthol | C38H47NO4 | 详情 | 详情 | |
| (XIV) | 35412 | 5-[(1R,3R)-2-benzyl-6,8-diisopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-8-isopropoxy-3-methyl-1-naphthyl methyl ether; (1R,3R)-2-benzyl-6,8-diisopropoxy-5-(4-isopropoxy-5-methoxy-7-methyl-1-naphthyl)-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline | C39H49NO4 | 详情 | 详情 | |
| (XV) | 35413 | (1R,3R)-2-benzyl-5-(4-hydroxy-5-methoxy-7-methyl-1-naphthyl)-1,3-dimethyl-1,2,3,4-tetrahydro-6,8-isoquinolinediol | C30H31NO4 | 详情 | 详情 |