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【结 构 式】 
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【分子编号】63596 【品名】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 【CA登记号】 |
【 分 子 式 】C25H32N2O6 【 分 子 量 】456.53896 【元素组成】C 65.77% H 7.06% N 6.14% O 21.03% |
合成路线1
该中间体在本合成路线中的序号：(III)The indole alkaloid catharanthine (I) is treated with m-chloroperbenzoic acid to provide the N-oxide (II). Condensation of (II) with the alkaloid vindoline (III) under Polonovski reaction conditions leads to the bis-indole adduct (IV), which is further reduced to the tetrahydropyridine compound (V). Catalytic hydrogenation of tetrahydropyridine (V) furnishes (VI). This is then oxidized to the N-oxide (VII) (3).
| 【1】 Mangeney, P.; Andriamialisoa, R.Z.; Langlois, N.; Langlois, Y.; Potier, P.; Preparation of vinblastine, vincristine, and leurosidine, antitumor alkaloids from Catharanthus spp. (Apocynaceae). J Am Chem Soc 1979, 101, 8, 2243. |
| 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) | 63594 | methyl 17-ethyl-3,13-diazapentacyclo[13.3.1.0~2,10~.0~4,9~.0~13,18~]nonadeca-2(10),4,6,8,16-pentaene-1-carboxylate | C21H24N2O2 | 详情 | 详情 | |
| (II) | 63595 | (1R,15R,18R)-17-ethyl-1-(methoxycarbonyl)-3-aza-13-azoniapentacyclo[13.3.1.0~2,10~.0~4,9~.0~13,18~]nonadeca-2(10),4,6,8,16-pentaen-13-olate | C21H24N2O3 | 详情 | 详情 | |
| (III) | 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 | |
| (IV) | 53597 | methyl (2S)-2-({(2R)-3-(acetylsulfanyl)-2-[(1R)-2,3-dihydro-1H-inden-1-yl]propanoyl}amino)-3-(1H-indol-3-yl)propanoate | n/a | C26H28N2O4S | 详情 | 详情 |
| (V) | 63598 | methyl (3aR,4R,5S,5aR,10bR,13aR)-4-(acetyloxy)-3a-ethyl-9-[(13S,15R)-17-ethyl-13-(methoxycarbonyl)-1,11-diazatetracyclo[13.3.1.0~4,12~.0~5,10~]nonadeca-4(12),5,7,9,16-pentaen-13-yl]-5-hydroxy-8-methoxy-6-methyl-3a,4,5,5a,6,11,12,13a-octahydro-1H-indolizino[8,1-cd]carbazole-5-carboxylate | C46H56N4O8 | 详情 | 详情 | |
| (VI) | 63599 | methyl (3aR,4R,5S,5aR,10bR,13aR)-4-(acetyloxy)-3a-ethyl-9-[(13S,15S,17S)-17-ethyl-13-(methoxycarbonyl)-1,11-diazatetracyclo[13.3.1.0~4,12~.0~5,10~]nonadeca-4(12),5,7,9-tetraen-13-yl]-5-hydroxy-8-methoxy-6-methyl-3a,4,5,5a,6,11,12,13a-octahydro-1H-indolizino[8,1-cd]carbazole-5-carboxylate | C46H58N4O8 | 详情 | 详情 | |
| (VII) | 63600 | (13S,15S,17S)-13-[(3aR,4R,5S,5aR,10bR,13aR)-4-(acetyloxy)-3a-ethyl-5-hydroxy-8-methoxy-5-(methoxycarbonyl)-6-methyl-3a,4,5,5a,6,11,12,13a-octahydro-1H-indolizino[8,1-cd]carbazol-9-yl]-17-ethyl-13-(methoxycarbonyl)-11-aza-1-azoniatetracyclo[13.3.1.0~4,12~.0~5,10~]nonadeca-4(12),5,7,9-tetraen-1-olate | C46H58N4O9 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)In a similar procedure, coupling of catharanthine-N-oxide (I) with vindoline (II) under Polonovski reaction conditions leads to the iminium salt (III). This is subsequently converted into the desired enamine (IV) employing NADH as the reducing reagent. Aeration of enamine (IV) in the presence of FeCl3, followed by reductive work up leads to the title compound (4).
| 【1】 Kutney, J.P.; Choi, L.S.L.; Nakano, J.; Tsukamoto, H.; McHugh, M.; Boulet, C.A.; A highly efficient and commercially important synthesis of the antitumor Catharantus alkaloids vinblastine and leurosidine from catharanthine and vindoline. Heterocycles 1988, 27, 8, 1845. |
| 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) | 63595 | (1R,15R,18R)-17-ethyl-1-(methoxycarbonyl)-3-aza-13-azoniapentacyclo[13.3.1.0~2,10~.0~4,9~.0~13,18~]nonadeca-2(10),4,6,8,16-pentaen-13-olate | C21H24N2O3 | 详情 | 详情 | |
| (II) | 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 | |
| (III) | 63597 | (13S,15R)-13-[(3aR,4R,5S,5aR,10bR,13aR)-4-(acetyloxy)-3a-ethyl-5-hydroxy-8-methoxy-5-(methoxycarbonyl)-6-methyl-3a,4,5,5a,6,11,12,13a-octahydro-1H-indolizino[8,1-cd]carbazol-9-yl]-17-ethyl-13-(methoxycarbonyl)-11-aza-1-azoniatetracyclo[13.3.1.0~4,12~.0~5,10~]nonadeca-1(18),4(12),5,7,9,16-hexaene | C48H55F3N4O10 | 详情 | 详情 | |
| (IV) | 63601 | methyl (3aR,4R,5S,5aR,10bR,13aR)-4-(acetyloxy)-3a-ethyl-9-[(13S,15S)-17-ethyl-13-(methoxycarbonyl)-1,11-diazatetracyclo[13.3.1.0~4,12~.0~5,10~]nonadeca-4(12),5,7,9,17-pentaen-13-yl]-5-hydroxy-8-methoxy-6-methyl-3a,4,5,5a,6,11,12,13a-octahydro-1H-indolizino[8,1-cd]carbazole-5-carboxylate | C46H56N4O8 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XV)Acidic hydrolysis of the mixture of diastereoisomeric acetonides (X) and (XI) leads to the respective diols, which are then separated by flash chromatography. After selective tosylation of the primary hydroxyl group of isomer (XII) with p-toluenesulfonic anhydride, the remaining tertiary hydroxyl is protected by silylation with trimethylsilyl triflate to furnish (XIII). Chlorination of (XIII) with tert-butyl hypochlorite leads to (XIV), which is then coupled to vindoline (XV) in the presence of AgBF4 to afford the bis-indolyl derivative (XVI) (5).
| 【1】 Kuehne, M.E.; Matson, P.A..; Bornmann, W.G.; Enantioselective syntheses of vinblastine, leurosidine, vincovaline, and 20'-epi-vincovaline. J Org Chem 1991, 56, 2, 513. |
| 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) | 63611 | methyl 4-[(4-ethyl-2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-3-(phenylmethyl)-2,3,3a,4,5,7-hexahydro-1H-pyrrolo[2,3-d]carbazole-6-carboxylate | C31H38N2O4 | 详情 | 详情 | |
| (XI) | 63612 | methyl 4-[(4-ethyl-2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-3-(phenylmethyl)-2,3,3a,4,5,7-hexahydro-1H-pyrrolo[2,3-d]carbazole-6-carboxylate | C31H38N2O4 | 详情 | 详情 | |
| (XII) | 63613 | methyl 4-[2-hydroxy-2-(hydroxymethyl)butyl]-3-(phenylmethyl)-2,3,3a,4,5,7-hexahydro-1H-pyrrolo[2,3-d]carbazole-6-carboxylate | C28H34N2O4 | 详情 | 详情 | |
| (XIII) | 63614 | methyl 4-{2-({[(4-methylphenyl)sulfonyl]oxy}methyl)-2-[(trimethylsilyl)oxy]butyl}-3-(phenylmethyl)-2,3,3a,4,5,7-hexahydro-1H-pyrrolo[2,3-d]carbazole-6-carboxylate | C38H48N2O6SSi | 详情 | 详情 | |
| (XIV) | 63615 | methyl 6-chloro-4-{2-({[(4-methylphenyl)sulfonyl]oxy}methyl)-2-[(trimethylsilyl)oxy]butyl}-3-(phenylmethyl)-2,3,3a,4,5,6-hexahydro-1H-pyrrolo[2,3-d]carbazole-6-carboxylate | C38H47ClN2O6SSi | 详情 | 详情 | |
| (XV) | 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 | |
| (XVI) | 63616 | methyl 4-(acetyloxy)-3a-ethyl-5-hydroxy-6-methyl-8-(methyloxy)-9-[6-[(methyloxy)carbonyl]-4-{2-({[(4-methylphenyl)sulfonyl]oxy}methyl)-2-[(trimethylsilyl)oxy]butyl}-3-(phenylmethyl)-2,3,3a,4,5,6-hexahydro-1H-pyrrolo[2,3-d]carbazol-6-yl]-3a,4,5,5a,6, | C63H78N4O12SSi | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XX)The tetracyclic intermediate (X) is coupled to vindoline (XX) upon treatment with p-nitrobenzyl chloroformate to furnish the bis-indole adduct (XXI) as a mixture of epimers at the carbomethoxy group. Isolation of the desired isomer, followed by acidic ketal hydrolysis leads to diol (XXII). This is then oxidized to the alpha-hydroxy aldehyde (XXIII) with SO3-pyridine in DMSO. Finally, hydrogenolysis of the p-nitrobenzyl carbamate, with concomitant intramolecular reductive amination of the aldehyde group produces the title bis-indole alkaloid
| 【1】 Magnus, P.; Mendoza, J.S.; Stamford, A.; Ladlow, M.; Willis, P.; Nonoxidative coupling methodology for the synthesis of the antitumor bisindole alkaloid vinblastine and a lower-half analogue: Solvent effect on the stereochemistry of the crucial C-15/C-18' bond. J Am Chem Soc 1992, 114, 26, 10232. |
| 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) | 63633 | methyl 2-[(2-ethyl-1,4-dioxaspiro[4.5]dec-2-yl)methyl]-2,3,6,11-tetrahydro-1H-indolizino[8,7-b]indole-11b(5H)-carboxylate | C27H36N2O4 | 详情 | 详情 | |
| (XX) | 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 | |
| (XXI) | 63641 | 7-methyl 3-[(4-nitrophenyl)methyl] 7-{4-(acetyloxy)-3a-ethyl-5-hydroxy-6-methyl-8-(methyloxy)-5-[(methyloxy)carbonyl]-3a,4,5,5a,6,11,12,13a-octahydro-1H-indolizino[8,1-cd]carbazol-9-yl}-5-[(2-ethyl-1,4-dioxaspiro[4.5]dec-2-yl)methyl]-1,4,5,6,7,8-hex | C60H73N5O14 | 详情 | 详情 | |
| (XXII) | 63642 | 7-methyl 3-[(4-nitrophenyl)methyl] 7-{4-(acetyloxy)-3a-ethyl-5-hydroxy-6-methyl-8-(methyloxy)-5-[(methyloxy)carbonyl]-3a,4,5,5a,6,11,12,13a-octahydro-1H-indolizino[8,1-cd]carbazol-9-yl}-5-[2-hydroxy-2-(hydroxymethyl)butyl]-1,4,5,6,7,8-hexahydroazoni | C54H65N5O14 | 详情 | 详情 | |
| (XXIII) | 63643 | 7-methyl 3-[(4-nitrophenyl)methyl] 7-{4-(acetyloxy)-3a-ethyl-5-hydroxy-6-methyl-8-(methyloxy)-5-[(methyloxy)carbonyl]-3a,4,5,5a,6,11,12,13a-octahydro-1H-indolizino[8,1-cd]carbazol-9-yl}-5-(2-formyl-2-hydroxybutyl)-1,4,5,6,7,8-hexahydroazonino[5,4-b] | C54H63N5O14 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XXIV)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 |
合成路线6
该中间体在本合成路线中的序号：(XXIV)Acid-catalyzed deprotection of the N-Boc and O-silyl groups of (XLV) leads to (XLVI). The primary hydroxyl group of (XLVI) is then tosylated to afford (XLVII). Subsequent esterification of the remaining tertiary hydroxyl with trifluoroacetic anhydride and pyridine yields trifluoroacetate (XLVIII). Chlorination of the indole nucleus of (XLVIII) with t-butyl hypochlorite furnishes the chloroindolenine (XLIX). Thisi is then coupled to vindoline (XXIII) in the presence of trifluoroacetic acid to form the bis-indole adduct (L) (8,9).
| 【1】 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. |
| 【2】 Schneider, C.; First de novo synthesis of the bisindole alkaloid vinblastine. Angew Chem. Int Ed 2002, 41, 22, 4217. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (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 | |
| (XLVI) | 63816 | 10-(tert-butyl) 9-methyl (5S,7R)-7-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-ethyl-5-hydroxy-3-[(4-nitrophenyl)sulfonyl]-2,3,4,5,6,7,8,9-octahydroazacycloundecino[5,4-b]indole-9,10(1H)-dicarboxylate | C48H59N3O10SSi | 详情 | 详情 | |
| (XLVII) | 63821 | methyl (5S,7R)-5-ethyl-5-hydroxy-7-(hydroxymethyl)-3-[(4-nitrophenyl)sulfonyl]-1,2,3,4,5,6,7,8,9,10-decahydroazacycloundecino[5,4-b]indole-9-carboxylate | C27H33N3O8S | 详情 | 详情 | |
| (XLVIII) | 63822 | methyl (5S,7R)-5-ethyl-5-hydroxy-7-({[(4-methylphenyl)sulfonyl]oxy}methyl)-3-[(4-nitrophenyl)sulfonyl]-1,2,3,4,5,6,7,8,9,10-decahydroazacycloundecino[5,4-b]indole-9-carboxylate | C34H39N3O10S2 | 详情 | 详情 | |
| (XLIX) | 63823 | methyl (5S,7R)-5-ethyl-7-({[(4-methylphenyl)sulfonyl]oxy}methyl)-3-[(4-nitrophenyl)sulfonyl]-5-[(2,2,2-trifluoroacetyl)oxy]-1,2,3,4,5,6,7,8,9,10-decahydroazacycloundecino[5,4-b]indole-9-carboxylate | C36H38F3N3O11S2 | 详情 | 详情 | |
| (L) | 63824 | methyl (5S,7R)-14b-chloro-5-ethyl-7-({[(4-methylphenyl)sulfonyl]oxy}methyl)-3-[(4-nitrophenyl)sulfonyl]-5-[(2,2,2-trifluoroacetyl)oxy]-1,2,3,4,5,6,7,8,10,14b-decahydroazacycloundecino[5,4-b]indole-9-carboxylate | C36H37ClF3N3O11S2 | 详情 | 详情 | |
| (LI) | 63825 | methyl (3aR,4R,5S,5aR,10bR,13aR)-4-(acetyloxy)-3a-ethyl-9-{(5S,7R,9S)-5-ethyl-9-(methoxycarbonyl)-7-({[(4-methylphenyl)sulfonyl]oxy}methyl)-3-[(4-nitrophenyl)sulfonyl]-5-[(2,2,2-trifluoroacetyl)oxy]-1,2,3,4,5,6,7,8,9,10-decahydroazacycloundecino[5,4 | C61H68F3N5O17S2 | 详情 | 详情 |