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【结 构 式】 
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【分子编号】18766 【品名】(1S,2S,5R)-2-(2-hydroxyethyl)-5-isopropenyl-2-methylcyclohexanol 【CA登记号】 |
【 分 子 式 】C12H22O2 【 分 子 量 】198.30548 【元素组成】C 72.68% H 11.18% O 16.14% |
合成路线1
该中间体在本合成路线中的序号：(X)Reduction of (-)-R-carvone (I) with LiAlH4 in Et2O at -78 C gave alcohol (II). Inversion of the hydroxyl group was then achieved by Mitsunobu reaction with 4-nitrobenzoic acid (III), followed by hydrolysis of the resulting 4-nitrobenzoate ester (IV) to give (V). Treatment of alcohol (V) with ethyl vinyl ether (VI) and N-bromosuccinimide produced the bromoacetal (VII). Subsequent intermolecular radical cyclization of (VII) with NaBH4 in the presence of a catalytic amount of Bu3SnCl and AIBN yielded cyclic acetal (VIII). Acidic hydrolysis of (VIII) followed by reduction of the resulting aldehyde (IX) with LiAlH4 provided diol (X). Protection of the primary alcohol group with trityl chloride in the presence of DMAP gave (XI), and subsequent oxidation of the secondary alcohol with pyridinum chlorochromate afforded ketone (XII). Further carbomethoxylation of (XII) by treatment with LDA and methyl cyanoformate yielded ketoester (XIII), which was reduced to alcohol (XIV) with NaBH4 in MeOH at 0 C. Then, alcohol (XIV) was converted to methyl ether (XV) by reaction with methyl iodide and NaH in DMF, and the ester group was reduced to alcohol (XVI) with LiAlH4 in Et2O at 0 C. Alcohol (XVI) was converted to mesylate (XVII) with methanesulfonyl chloride and Et3N.
| 【1】 Tsukuda, T.; Watanabe, M.; Ontsuka, H.; Hattori, K.; Shirai, M.; Shimma, N.; Synthesis of novel antifungal agents (2). Bioorg Med Chem Lett 1998, 8, 14, 1825. |
| 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) | 13386 | (5R)-5-Isopropenyl-2-methyl-2-cyclohexen-1-one; L-(-)-Carvone | 6485-40-1 | C10H14O | 详情 | 详情 |
| (II) | 18758 | (1R,5R)-5-isopropenyl-2-methyl-2-cyclohexen-1-ol | C10H16O | 详情 | 详情 | |
| (III) | 18119 | 4-nitrobenzoic acid; p-nitrobenzoic acid | 62-23-7 | C7H5NO4 | 详情 | 详情 |
| (IV) | 18760 | (1S,5R)-5-isopropenyl-2-methyl-2-cyclohexen-1-yl 4-nitrobenzoate | C17H19NO4 | 详情 | 详情 | |
| (V) | 18761 | (1S,5R)-5-isopropenyl-2-methyl-2-cyclohexen-1-ol | C10H16O | 详情 | 详情 | |
| (VI) | 18762 | 1-Ethoxyethylene; Ethyl vinyl ether；Ethoxyethene | 109-92-2 | C4H8O | 详情 | 详情 |
| (VII) | 18763 | 2-bromo-1-ethoxyethyl (1S,5R)-5-isopropenyl-2-methyl-2-cyclohexen-1-yl ether; (4R,6S)-6-(2-bromo-1-ethoxyethoxy)-4-isopropenyl-1-methyl-1-cyclohexene | C14H23BrO2 | 详情 | 详情 | |
| (VIII) | 18764 | (3aS,6R,7aS)-2-ethoxy-6-isopropenyl-3a-methyloctahydro-1-benzofuran; (3aS,6R,7aS)-6-isopropenyl-3a-methyloctahydro-1-benzofuran-2-yl ethyl ether | C14H24O2 | 详情 | 详情 | |
| (IX) | 18765 | 2-[(1S,2S,4R)-2-hydroxy-4-isopropenyl-1-methylcyclohexyl]acetaldehyde | C12H20O2 | 详情 | 详情 | |
| (X) | 18766 | (1S,2S,5R)-2-(2-hydroxyethyl)-5-isopropenyl-2-methylcyclohexanol | C12H22O2 | 详情 | 详情 | |
| (XI) | 18767 | (1S,2S,5R)-5-isopropenyl-2-methyl-2-[2-(trityloxy)ethyl]cyclohexanol | C31H36O2 | 详情 | 详情 | |
| (XII) | 18768 | (2S,5R)-5-isopropenyl-2-methyl-2-[2-(trityloxy)ethyl]cyclohexanone | C31H34O2 | 详情 | 详情 | |
| (XIII) | 18769 | methyl (3S,6R)-6-isopropenyl-3-methyl-2-oxo-3-[2-(trityloxy)ethyl]cyclohexanecarboxylate | C33H36O4 | 详情 | 详情 | |
| (XIV) | 18770 | methyl (1S,2R,3S,6R)-2-hydroxy-6-isopropenyl-3-methyl-3-[2-(trityloxy)ethyl]cyclohexanecarboxylate | C33H38O4 | 详情 | 详情 | |
| (XV) | 18771 | methyl (1S,2R,3S,6R)-6-isopropenyl-2-methoxy-3-methyl-3-[2-(trityloxy)ethyl]cyclohexanecarboxylate | C34H40O4 | 详情 | 详情 | |
| (XVI) | 18772 | [(1R,2R,3S,6R)-6-isopropenyl-2-methoxy-3-methyl-3-[2-(trityloxy)ethyl]cyclohexyl]methanol | C33H40O3 | 详情 | 详情 | |
| (XVII) | 18773 | [(1R,2R,3S,6R)-6-isopropenyl-2-methoxy-3-methyl-3-[2-(trityloxy)ethyl]cyclohexyl]methyl methanesulfonate | C34H42O5S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)Reduction of (-)-R-carvone (I) with LiAlH4 in Et2O at -78 C gave alcohol (II). Inversion of the hydroxyl group was then achieved by Mitsunobu reaction with 4-nitrobenzoic acid (III), followed by hydrolysis of the resulting 4-nitrobenzoate ester (IV) to give (V). Treatment of alcohol (V) with ethyl vinyl ether (VI) and N-bromosuccinimide produced the bromoacetal (VII). Subsequent intermolecular radical cyclization of (VII) with NaBH4 in the presence of a catalytic amount of Bu3SnCl and AIBN yielded cyclic acetal (VIII). Acidic hydrolysis of (VIII) followed by reduction of the resulting aldehyde (IX) with LiAlH4 provided diol (X). Protection of the primary alcohol group with trityl chloride in the presence of DMAP gave (XI), and subsequent oxidation of the secondary alcohol with pyridinum chlorochromate afforded ketone (XII). Further carbomethoxylation of (XII) by treatment with LDA and methyl cyanoformate yielded ketoester (XIII), which was reduced to alcohol (XIV) with NaBH4 in MeOH at 0 C. Then, alcohol (XIV) was converted to methyl ether (XV) by reaction with methyl iodide and NaH in DMF, and the ester group was reduced to alcohol (XVI) with LiAlH4 in Et2O at 0 C. Alcohol (XVI) was converted to mesylate (XVII) with methanesulfonyl chloride and Et3N.
| 【1】 Tsukuda, T.; Watanabe, M.; Ontsuka, H.; Hattori, K.; Shirai, M.; Shimma, N.; Synthesis of novel antifungal agents (2). Bioorg Med Chem Lett 1998, 8, 14, 1825. |
| 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) | 13386 | (5R)-5-Isopropenyl-2-methyl-2-cyclohexen-1-one; L-(-)-Carvone | 6485-40-1 | C10H14O | 详情 | 详情 |
| (II) | 18758 | (1R,5R)-5-isopropenyl-2-methyl-2-cyclohexen-1-ol | C10H16O | 详情 | 详情 | |
| (III) | 18119 | 4-nitrobenzoic acid; p-nitrobenzoic acid | 62-23-7 | C7H5NO4 | 详情 | 详情 |
| (IV) | 18760 | (1S,5R)-5-isopropenyl-2-methyl-2-cyclohexen-1-yl 4-nitrobenzoate | C17H19NO4 | 详情 | 详情 | |
| (V) | 18761 | (1S,5R)-5-isopropenyl-2-methyl-2-cyclohexen-1-ol | C10H16O | 详情 | 详情 | |
| (VI) | 18762 | 1-Ethoxyethylene; Ethyl vinyl ether；Ethoxyethene | 109-92-2 | C4H8O | 详情 | 详情 |
| (VII) | 18763 | 2-bromo-1-ethoxyethyl (1S,5R)-5-isopropenyl-2-methyl-2-cyclohexen-1-yl ether; (4R,6S)-6-(2-bromo-1-ethoxyethoxy)-4-isopropenyl-1-methyl-1-cyclohexene | C14H23BrO2 | 详情 | 详情 | |
| (VIII) | 18764 | (3aS,6R,7aS)-2-ethoxy-6-isopropenyl-3a-methyloctahydro-1-benzofuran; (3aS,6R,7aS)-6-isopropenyl-3a-methyloctahydro-1-benzofuran-2-yl ethyl ether | C14H24O2 | 详情 | 详情 | |
| (IX) | 18765 | 2-[(1S,2S,4R)-2-hydroxy-4-isopropenyl-1-methylcyclohexyl]acetaldehyde | C12H20O2 | 详情 | 详情 | |
| (X) | 18766 | (1S,2S,5R)-2-(2-hydroxyethyl)-5-isopropenyl-2-methylcyclohexanol | C12H22O2 | 详情 | 详情 | |
| (XI) | 18767 | (1S,2S,5R)-5-isopropenyl-2-methyl-2-[2-(trityloxy)ethyl]cyclohexanol | C31H36O2 | 详情 | 详情 | |
| (XII) | 18768 | (2S,5R)-5-isopropenyl-2-methyl-2-[2-(trityloxy)ethyl]cyclohexanone | C31H34O2 | 详情 | 详情 | |
| (XIII) | 18769 | methyl (3S,6R)-6-isopropenyl-3-methyl-2-oxo-3-[2-(trityloxy)ethyl]cyclohexanecarboxylate | C33H36O4 | 详情 | 详情 | |
| (XIV) | 18770 | methyl (1S,2R,3S,6R)-2-hydroxy-6-isopropenyl-3-methyl-3-[2-(trityloxy)ethyl]cyclohexanecarboxylate | C33H38O4 | 详情 | 详情 | |
| (XV) | 18771 | methyl (1S,2R,3S,6R)-6-isopropenyl-2-methoxy-3-methyl-3-[2-(trityloxy)ethyl]cyclohexanecarboxylate | C34H40O4 | 详情 | 详情 | |
| (XVI) | 18772 | [(1R,2R,3S,6R)-6-isopropenyl-2-methoxy-3-methyl-3-[2-(trityloxy)ethyl]cyclohexyl]methanol | C33H40O3 | 详情 | 详情 | |
| (XVII) | 18773 | [(1R,2R,3S,6R)-6-isopropenyl-2-methoxy-3-methyl-3-[2-(trityloxy)ethyl]cyclohexyl]methyl methanesulfonate | C34H42O5S | 详情 | 详情 |