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【结 构 式】 
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【分子编号】63768 【品名】tert-butyl 3-(2-hydroxyethyl)-2-[1-(methoxycarbonyl)vinyl]-6-[(methylsulfonyl)oxy]-1H-indole-1-carboxylate 【CA登记号】 |
【 分 子 式 】C20H25NO8S 【 分 子 量 】439.48644 【元素组成】C 54.66% H 5.73% N 3.19% O 29.12% S 7.3% |
合成路线1
该中间体在本合成路线中的序号：(XVII)Treatment of 7-mesyloxyquinoline (IX) with thiophosgene, followed by reduction with NaBH4 gives rise to isothiocyanate (X). After protection of the hydroxyl group of (X) as the tetrahydropyranyl ether (XI), nucleophilic addition of the anion of benzyl methyl malonate to the isothiocyanate group affords thioanilide (XII). The radical cyclization of (XII) in the presence of AIBN and Bu3SnH furnishes indole (XII). After protection of indole (XIII) as the N-Boc derivative (XIV), the benzyl ester group is removed by hydrogenolysis, producing the mono-methyl malonate (XV). Decarboxylative Mannich reaction of (XV) with formaldehyde and dimethylamine leads to the indolylacrylate (XVI). The tetrahydropyranyl group is then selectively removed by means of CSA in MeOH to provide tryptophol (XVII) (8, 9).
| 【1】 Schneider, C.; First de novo synthesis of the bisindole alkaloid vinblastine. Angew Chem. Int Ed 2002, 41, 22, 4217. |
| 【2】 Yokoshima, S.; Ueda, T.; Kobayashi, S.; Sato, A.; Kuboyama, T.; Tokuyama, H.; Fukuyama, T.; Stereocontrolled total synthesis of (+)-vinblastine. J Am Chem Soc 2002, 124, 10, 2137. |
| 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) | 63761 | 4-[(Z)-3-hydroxy-1-propenyl]-3-isothiocyanatophenyl methanesulfonate | C11H11NO4S2 | 详情 | 详情 | |
| (XI) | 63762 | 3-isothiocyanato-4-[(Z)-3-(tetrahydro-2H-pyran-2-yloxy)-1-propenyl]phenyl methanesulfonate | C16H19NO5S2 | 详情 | 详情 | |
| (XII) | 63763 | 1-benzyl 3-methyl 2-({5-[(methylsulfonyl)oxy]-2-[(Z)-3-(tetrahydro-2H-pyran-2-yloxy)-1-propenyl]anilino}carbothioyl)malonate | C27H31NO9S2 | 详情 | 详情 | |
| (XIII) | 63764 | 1-benzyl 3-methyl 2-{6-[(methylsulfonyl)oxy]-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-indol-2-yl}malonate | C27H31NO9S | 详情 | 详情 | |
| (XIV) | 63765 | 1-benzyl 3-methyl 2-{1-(tert-butoxycarbonyl)-6-[(methylsulfonyl)oxy]-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-indol-2-yl}malonate | C32H39NO11S | 详情 | 详情 | |
| (XV) | 63766 | 2-{1-(tert-butoxycarbonyl)-6-[(methylsulfonyl)oxy]-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-indol-2-yl}-3-methoxy-3-oxopropanoic acid | C25H33NO11S | 详情 | 详情 | |
| (XVI) | 63767 | tert-butyl 2-[1-(methoxycarbonyl)vinyl]-6-[(methylsulfonyl)oxy]-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-indole-1-carboxylate | C25H33NO9S | 详情 | 详情 | |
| (XVII) | 63768 | tert-butyl 3-(2-hydroxyethyl)-2-[1-(methoxycarbonyl)vinyl]-6-[(methylsulfonyl)oxy]-1H-indole-1-carboxylate | C20H25NO8S | 详情 | 详情 | |
| (LX) | 63760 | 7-quinolinyl methanesulfonate | C10H9NO3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVII)Mitsunobu coupling between tryptophol (XVII) and sulfonamide (VIII) yields the N-sulfonyl tryptamine derivative (XVIII). Hydration of the cyclic enol ether, with simultaneous Boc group cleavage under acidic conditions affords lactol (XIX). Subsequent deprotection of the dinitrobenzenesulfonyl group of (XIX) with piperidine in MeOH proceeds with rearrangement of the deprotected amino lactol to the cyclic hydroxy enamine (XX). This, upon further heating, undergoes a Diels-Alder type reaction to afford the pentacyclic vindoline ring system (XXI). Following a previously reported synthetic pathway for (XXI), regioselective elimination of the secondary alcohol function, followed by protective group exchange at the phenolic hydroxyl, and oxidation with benzeneseleninic anhydride leads to the C4-alcohol (XXII). Further introduction of the C3-hydroxyl with m chloroperbenzoic acid, and reduction of the resultant imine with NaBH3CN provides diol (XXIII). After reductive methylation of the indoline N of (XXIII) with HCHO/NaBH3CN, acetylation of the secondary hydroxyl group produces ( ) vindoline (XXIII) (8, 9).
| 【1】 Schneider, C.; First de novo synthesis of the bisindole alkaloid vinblastine. Angew Chem. Int Ed 2002, 41, 22, 4217. |
| 【2】 Yokoshima, S.; Ueda, T.; Kobayashi, S.; Sato, A.; Kuboyama, T.; Tokuyama, H.; Fukuyama, T.; Stereocontrolled total synthesis of (+)-vinblastine. J Am Chem Soc 2002, 124, 10, 2137. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 63759 | N-{[(2S)-4-ethyl-2,3-dihydro-2-furanyl]methyl}-2,4-dinitrobenzenesulfonamide | C13H15N3O7S | 详情 | 详情 | |
| (XVII) | 63768 | tert-butyl 3-(2-hydroxyethyl)-2-[1-(methoxycarbonyl)vinyl]-6-[(methylsulfonyl)oxy]-1H-indole-1-carboxylate | C20H25NO8S | 详情 | 详情 | |
| (XVIII) | 63769 | tert-butyl 3-[2-([(2,4-dinitrophenyl)sulfonyl]{[(2S)-4-ethyl-2,3-dihydro-2-furanyl]methyl}amino)ethyl]-2-[1-(methoxycarbonyl)vinyl]-6-[(methylsulfonyl)oxy]-1H-indole-1-carboxylate | C33H38N4O14S2 | 详情 | 详情 | |
| (XIX) | 63770 | methyl 2-{3-[2-([(2,4-dinitrophenyl)sulfonyl]{[(2S)-4-ethyl-5-hydroxytetrahydro-2-furanyl]methyl}amino)ethyl]-6-[(methylsulfonyl)oxy]-1H-indol-2-yl}acrylate | C28H32N4O13S2 | 详情 | 详情 | |
| (XX) | 63771 | methyl 2-{3-{2-[(3S)-5-ethyl-3-hydroxy-3,4-dihydro-1(2H)-pyridinyl]ethyl}-6-[(methylsulfonyl)oxy]-1H-indol-2-yl}acrylate | C22H28N2O6S | 详情 | 详情 | |
| (XXI) | 63772 | methyl (2S,3aR,10bR,13aS)-3a-ethyl-2-hydroxy-8-[(methylsulfonyl)oxy]-2,3,3a,4,6,11,12,13a-octahydro-1H-indolizino[8,1-cd]carbazole-5-carboxylate | C22H28N2O6S | 详情 | 详情 | |
| (XXII) | 63773 | methyl (3aR,4R,10bR,13aR)-3a-ethyl-4-hydroxy-8-methoxy-3a,4,6,11,12,13a-hexahydro-1H-indolizino[8,1-cd]carbazole-5-carboxylate | C22H26N2O4 | 详情 | 详情 | |
| (XXIII) | 63774 | methyl (3aR,4R,5S,5aR,10bS,13aR)-3a-ethyl-4,5-dihydroxy-8-methoxy-3a,4,5,5a,6,11,12,13a-octahydro-1H-indolizino[8,1-cd]carbazole-5-carboxylate | C22H28N2O5 | 详情 | 详情 | |
| (XXIV) | 63596 | methyl 4-(acetyloxy)-3a-ethyl-5-hydroxy-6-methyl-8-(methyloxy)-3a,4,5,5a,6,11,12,13a-octahydro-1H-indolizino[8,1-cd]carbazole-5-carboxylate | C25H32N2O6 | 详情 | 详情 |