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【结 构 式】 
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【分子编号】48480 【品名】methyl (5R,7S)-5-[(2R)-2-(1,3-dioxolan-2-yl)-4-methoxybutyl]-1,2,3,4,5,6,7,8-octahydroazonino[5,4-b]indole-7-carboxylate 【CA登记号】 |
【 分 子 式 】C24H34N2O5 【 分 子 量 】430.54444 【元素组成】C 66.95% H 7.96% N 6.51% O 18.58% |
合成路线1
该中间体在本合成路线中的序号：(VIa)Condensation of the indoloazepine (I) bearing a chiral N-(1-naphthylethyl) substituent with 4-(1,3-dioxolan-2-yl)-6-methoxyhexanal (II) through a secodine-type intramolecular Diels-Alder reaction generated the epimeric mixture of pyrrolocarbazoles (III) along with minor amounts of their diastereoisomers (IV). The subsequent reductive ring cleavage of this mixture yielded the corresponding mixture of tricyclic compounds (V). Hydrogenolysis of the N-naphthylethyl group of (V), followed by chromatographic separation, gave the enantiomerically enriched secondary amines (VI). Acetal hydrolysis of (VI) with simultaneous cyclization of a transient aminoaldehyde provided the tetracyclic enamine (VII). Rearrangement of this enamine in refluxing toluene furnished the desired compound in 76% ee, which was further enriched to >98% ee by fractional crystallization.
| 【1】 Kuehne, M.E.; et al.; Enantioselective syntheses of coronaridine and 18-methoxycoronaridine. Tetrahedron 2001, 57, 11, 2085. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIIa) | 48475 | methyl (3aS,4R,11bR)-4-[(2S)-2-(1,3-dioxolan-2-yl)-4-methoxybutyl]-3-[(1R)-1-(1-naphthyl)ethyl]-2,3,3a,4,5,7-hexahydro-1H-pyrrolo[2,3-d]carbazole-6-carboxylate | C36H42N2O5 | 详情 | 详情 | |
| (IIIb) | 48476 | methyl (3aS,4R,11bR)-4-[(2R)-2-(1,3-dioxolan-2-yl)-4-methoxybutyl]-3-[(1R)-1-(1-naphthyl)ethyl]-2,3,3a,4,5,7-hexahydro-1H-pyrrolo[2,3-d]carbazole-6-carboxylate | C36H42N2O5 | 详情 | 详情 | |
| (IVa) | 48477 | methyl (3aR,4S,11bS)-4-[(2S)-2-(1,3-dioxolan-2-yl)-4-methoxybutyl]-3-[(1R)-1-(1-naphthyl)ethyl]-2,3,3a,4,5,7-hexahydro-1H-pyrrolo[2,3-d]carbazole-6-carboxylate | C36H42N2O5 | 详情 | 详情 | |
| (IVb) | 48478 | methyl (3aR,4S,11bS)-4-[(2R)-2-(1,3-dioxolan-2-yl)-4-methoxybutyl]-3-[(1R)-1-(1-naphthyl)ethyl]-2,3,3a,4,5,7-hexahydro-1H-pyrrolo[2,3-d]carbazole-6-carboxylate | C36H42N2O5 | 详情 | 详情 | |
| (VIa) | 48480 | methyl (5R,7S)-5-[(2R)-2-(1,3-dioxolan-2-yl)-4-methoxybutyl]-1,2,3,4,5,6,7,8-octahydroazonino[5,4-b]indole-7-carboxylate | C24H34N2O5 | 详情 | 详情 | |
| (VIb) | 48481 | methyl (5R,7S)-5-[(2S)-2-(1,3-dioxolan-2-yl)-4-methoxybutyl]-1,2,3,4,5,6,7,8-octahydroazonino[5,4-b]indole-7-carboxylate | C24H34N2O5 | 详情 | 详情 | |
| (I) | 48473 | methyl 3-[(1R)-1-(1-naphthyl)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5-carboxylate | C26H26N2O2 | 详情 | 详情 | |
| (II) | 48474 | 4-(1,3-dioxolan-2-yl)-6-methoxyhexanal | C10H18O4 | 详情 | 详情 | |
| (V) | 48479 | methyl 5-[2-(1,3-dioxolan-2-yl)-4-methoxybutyl]-3-[(1R)-1-(1-naphthyl)ethyl]-1,2,3,4,5,6,7,8-octahydroazonino[5,4-b]indole-7-carboxylate | C36H44N2O5 | 详情 | 详情 | |
| (VII) | 48482 | methyl (13R,15S)-17-(2-methoxyethyl)-1,11-diazatetracyclo[13.3.1.0(4,12).0(5,10)]nonadeca-4(12),5,7,9,17-pentaene-13-carboxylate | C22H28N2O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIa)In an alternative procedure, aldehyde (II) was condensed with the indoloazepine (VIII) bearing a chiral N-alpha-ferrocenylethyl substituent to provide an equimolecular mixture of two separable C-20 epimeric diastereomers (IX) and (X), each accompanied by a minor diastereoisomeric byproduct. Cleavage of the ferrocenyl substituent with HOAc at 70 C provided the secondary amines (XI) and (XII). In this cleavage, the C-3,C-7 epimeric products were formed in 12% yield and were separated by chromatography. The major secondary amines (XI) and (XII) were N-benzylated to provide the corresponding tertiary amines (XIII). Reductive ring cleavage, followed by hydrogenolysis of the N-benzyl group, then gave the tricyclic compounds (VI), which were cyclized and rearranged as above.
| 【1】 Kuehne, M.E.; et al.; Enantioselective syntheses of coronaridine and 18-methoxycoronaridine. Tetrahedron 2001, 57, 11, 2085. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIa) | 48480 | methyl (5R,7S)-5-[(2R)-2-(1,3-dioxolan-2-yl)-4-methoxybutyl]-1,2,3,4,5,6,7,8-octahydroazonino[5,4-b]indole-7-carboxylate | C24H34N2O5 | 详情 | 详情 | |
| (VIb) | 48481 | methyl (5R,7S)-5-[(2S)-2-(1,3-dioxolan-2-yl)-4-methoxybutyl]-1,2,3,4,5,6,7,8-octahydroazonino[5,4-b]indole-7-carboxylate | C24H34N2O5 | 详情 | 详情 | |
| (XIIIa) | 48488 | methyl (3aS,4R,11bR)-3-benzyl-4-[(2R)-2-(1,3-dioxolan-2-yl)-4-methoxybutyl]-2,3,3a,4,5,7-hexahydro-1H-pyrrolo[2,3-d]carbazole-6-carboxylate | C31H38N2O5 | 详情 | 详情 | |
| (XIIIb) | 48489 | methyl (3aS,4R,11bR)-3-benzyl-4-[(2S)-2-(1,3-dioxolan-2-yl)-4-methoxybutyl]-2,3,3a,4,5,7-hexahydro-1H-pyrrolo[2,3-d]carbazole-6-carboxylate | C31H38N2O5 | 详情 | 详情 | |
| (II) | 48474 | 4-(1,3-dioxolan-2-yl)-6-methoxyhexanal | C10H18O4 | 详情 | 详情 | |
| (VIII) | 48483 | C38H39FeN2O2P | 详情 | 详情 | ||
| (IX) | 48484 | C48H55FeN2O5P | 详情 | 详情 | ||
| (X) | 48485 | C48H55FeN2O5P | 详情 | 详情 | ||
| (XI) | 48486 | methyl (3aS,4R,11bR)-4-[(2R)-2-(1,3-dioxolan-2-yl)-4-methoxybutyl]-2,3,3a,4,5,7-hexahydro-1H-pyrrolo[2,3-d]carbazole-6-carboxylate | C24H32N2O5 | 详情 | 详情 | |
| (XII) | 48487 | methyl (3aS,4R,11bR)-4-[(2S)-2-(1,3-dioxolan-2-yl)-4-methoxybutyl]-2,3,3a,4,5,7-hexahydro-1H-pyrrolo[2,3-d]carbazole-6-carboxylate | C24H32N2O5 | 详情 | 详情 |