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【结 构 式】

【药物名称】Vinblastine sulfate, 29060-LE, NSC-49842, Velbe, Velsar, Velban

【化学名称】Vincaleukoblastine sulfate

【CA登记号】143-67-9, 865-21-4 (free base)

【 分 子 式 】C46H60N4O13S

【 分 子 量 】909.0741

【开发单位】Janssen (Originator), Lilly (Licensee)

【药理作用】ONCOLYTIC DRUGS, Vinca Alkaloids

合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17

合成路线1

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).

参考文献 中间体
【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

N-Oxide (VII) is subjected to a new Polonovski rearrangement, leading to enamine (VIII). Exposure of (VIII) to thallium triacetate gives rise to the iminium salt (IX), which undergoes further reduction and acetate ester hydrolysis in the presence of NaBH4 to yield the desired compound (3).

参考文献 中间体
【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
(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
(VIII) 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
(IX) 63602 (13S,15R,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-(acetyloxy)-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-pentaene C50H62N4O12 详情 详情

合成路线3

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).

参考文献 中间体
【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4

In an alternative synthesis, which does not utilize the alkaloid catharanthine, Sharpless asymmetric epoxidation of 2-ethyl-2-propenol (I) in the presence of ( )-diethyl tartrate provides (R)-2-ethyl-2,3-epoxypropanol (II). Subsequent addition of allylmagnesium chloride (III) to epoxide (II) leads to diol (IV), which is further protected as the corresponding acetonide (V) with 2,2 dimethoxypropane and p-TsOH. Ozonolysis of the terminal olefin (V) gives rise to aldehyde (VI). Condensation of aldehyde (VI) with the indoloazapine (VII) furnishes the bridged azepine (VIII) as a diastereomeric mixture. Without isolation, this mixture of amines is N-alkylated with benzyl bromide, and the resultant ammonium salts (IX) are subjected to rearrangement in boiling MeOH in the presence of Et3N to provide an equimolecular mixture of the tetracyclic diastereoisomers (X) and (XI) (5).

参考文献 中间体
【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
(I) 63603 2-ethyl-2-propen-1-ol C5H10O 详情 详情
(II) 63604 (2-ethyl-2-oxiranyl)methanol C5H10O2 详情 详情
(III) 61128 　 C4H8 详情 详情
(IV) 63605 2-ethyl-5-hexene-1,2-diol C8H16O2 详情 详情
(V) 63606 4-(3-butenyl)-4-ethyl-2,2-dimethyl-1,3-dioxolane C11H20O2 详情 详情
(VI) 63607 3-(4-ethyl-2,2-dimethyl-1,3-dioxolan-4-yl)propanal C10H18O3 详情 详情
(VII) 63608 methyl 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5-carboxylate C14H16N2O2 详情 详情
(VIII) 63609 methyl 15-{2-[(4S)-4-ethyl-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl}-8,12-diazatetracyclo[10.2.1.0~1,9~.0~2,7~]pentadeca-2,4,6,9-tetraene-10-carboxylate C24H32N2O4 详情 详情
(IX) 63610 12-benzyl-15-{2-[(4S)-4-ethyl-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl}-10-(methoxycarbonyl)-8-aza-12-azoniatetracyclo[10.2.1.0~1,9~.0~2,7~]pentadeca-2,4,6,9-tetraene bromide C31H39BrN2O4 详情 详情
(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

合成路线5

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).

参考文献 中间体
【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6

Reductive opening of (XVI) with KBH4 in AcOH produces the indoloazonine system (XVII). Intramolecular cyclization of the amino tosylate (XVII) in refluxing MeOH leads to the quaternary salt (XVIII). The N-benzyl group of (XVIII) is then removed by hydrogenolysis over Pd/C to give the silyl ether of vinblastine (XIX). The trimethylsilyl group of (XIX) is finally removed with tetrabutylammonium fluoride to furnish the target compound (5).

参考文献 中间体
【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
(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
(XVII) 63617 methyl (3aR,4R,5S,5aR,10bR,13aR)-4-(acetyloxy)-9-((5R,7S)-3-benzyl-7-(methoxycarbonyl)-5-{(2S)-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)-2-[(trimethylsilyl)oxy]butyl}-1,2,3,4,5,6,7,8-octahydroazonino[5,4-b]indol-7-yl)-3a-ethyl-5-hydroxy-8-methoxy-6-methyl-3a,4,5,5a,6,11,12,13a-octahydro-1H-indolizino[8,1-cd]carbazole-5-carboxylate C63H80N4O12SSi 详情 详情
(XVIII) 63618 (13S,15R,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]-1-benzyl-17-ethyl-13-(methoxycarbonyl)-17-[(trimethylsilyl)oxy]-11-aza-1-azoniatetracyclo[13.3.1.0~4,12~.0~5,10~]nonadeca-4(12),5,7,9-tetraene C63H80N4O12SSi 详情 详情
(XIX) 63619 methyl (3aR,4R,5S,5aR,10bR,13aR)-4-(acetyloxy)-3a-ethyl-9-[(13S,15R,17S)-17-ethyl-13-(methoxycarbonyl)-17-[(trimethylsilyl)oxy]-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 C49H66N4O9Si 详情 详情

合成路线7

In an improved method for the preparation of intermediate (XI), indolodiazepine (I) is condensed with the chiral ferrocenylethyl acetate (II) to produce the N-alkylated compound (III) as an inseparable mixture of diastereoisomers. Subsequent condensation of (III) with aldehyde (IV) and rearrangement in refluxing benzene gives rise to the tetracyclic compound (V) as a single diastereoisomer. Acetolysis of (V) provides amine (VI) along with minor amounts of a partly epimerized compound, which can be removed by chromatography. Then, alkylation of (VI) with benzyl bromide yields the key synthetic intermediate (XI) (6).

参考文献 中间体
【1】 Kuehne, M.E.; Bandarage, U.K.; An alternative enantioselective generation of intermediates in the total synthesis of vinblastine: Enantioselection in secodine-type reactions induced by alpha-ferrocenylethyl N-substituents. J Org Chem 1996, 61, 3, 1175.
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) 63608 methyl 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5-carboxylate C14H16N2O2 详情 详情
(II) 63620 　 C26H25FeO2P 详情 详情
(III) 63621 　 C39H41N2O2P 详情 详情
(IV) 63607 3-(4-ethyl-2,2-dimethyl-1,3-dioxolan-4-yl)propanal C10H18O3 详情 详情
(V) 63622 　 C48H55FeN2O4P 详情 详情
(VI) 63623 methyl 4-[(4-ethyl-2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2,3,3a,4,5,7-hexahydro-1H-pyrrolo[2,3-d]carbazole-6-carboxylate C24H32N2O4 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

合成路线8

In a nonoxidative coupling sytrategy, the required tetracyclic precursor (X) has been prepared by two methods. Alkylation of thiolactam (I) with 2 (bromomethyl)-1-butene (II) gives the thioiminium salt (III), which undergoes thio-Claisen rearrangement in the presence of DBU in THF to produce (IV) as a mixture of cis and trans isomers. After conversion of thiolactams (IV) into the corresponding lactams with m-chloroperoxybenzoic acid (mCPBA), the desired isomer (V) is isolated employing preparative HPLC. Double bond dihydroxylation with N-methylmorpholine-N-oxide in the presence of a catalytic amount of OsO4 leads to diol (VI) as a diastereomeric mixture. Protection of diols (VI) with 1-methoxycyclohexene (VII) affords the corresponding mixture of cyclohexylidene ketals (VIII). After conversion of (VIII) to the respective thiolactams with Lawesson's reagent in hot toluene, separation of isomers employing preparative HPLC furnishes thiolactam (IX). Then, desulfuration of thiolactam (IX) by means of Raney nickel gives rise to intermediate (X) (7).

参考文献 中间体
【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
(I) 63624 methyl 3-thioxo-2,3,6,11-tetrahydro-1H-indolizino[8,7-b]indole-11b(5H)-carboxylate C16H16N2O2S 详情 详情
(II) 63625 　 C5H9Br 详情 详情
(III) 63626 {11b-[(methyloxy)carbonyl]-1,2,5,6,11,11b-hexahydro-3H-indolizino[8,7-b]indol-3-ylidene}(2-ethyl-2-propenyl)sulfonium bromide C21H25BrN2O2S 详情 详情
(IV) 63627 methyl 2-(2-ethyl-2-propenyl)-3-thioxo-2,3,6,11-tetrahydro-1H-indolizino[8,7-b]indole-11b(5H)-carboxylate C21H24N2O2S 详情 详情
(V) 63628 methyl 2-(2-ethyl-2-propenyl)-3-oxo-2,3,6,11-tetrahydro-1H-indolizino[8,7-b]indole-11b(5H)-carboxylate C21H24N2O3 详情 详情
(VI) 63629 methyl 2-[2-hydroxy-2-(hydroxymethyl)butyl]-3-oxo-2,3,6,11-tetrahydro-1H-indolizino[8,7-b]indole-11b(5H)-carboxylate C21H26N2O5 详情 详情
(VII) 63630 1-(methyloxy)-1-cyclohexene; 1-cyclohexen-1-yl methyl ether C7H12O 详情 详情
(VIII) 63631 methyl 2-[(2-ethyl-1,4-dioxaspiro[4.5]dec-2-yl)methyl]-3-oxo-2,3,6,11-tetrahydro-1H-indolizino[8,7-b]indole-11b(5H)-carboxylate C27H34N2O5 详情 详情
(IX) 63632 methyl 2-[(2-ethyl-1,4-dioxaspiro[4.5]dec-2-yl)methyl]-3-thioxo-2,3,6,11-tetrahydro-1H-indolizino[8,7-b]indole-11b(5H)-carboxylate C27H34N2O4S 详情 详情
(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

合成路线9

In an alternative, stereospecific synthesis of (X), Sharpless asymmetric epoxidation of 2-ethyl-2-propen-1-ol (XI) in the presence of (-)-diethyl tartrate provides the (R)-epoxide (XII). Ring opening of (XII) with sodium thiophenoxide produces diol (XIII), which is further protected with 1-methoxycyclohexene (VII), yielding ketal (XIV). Sulfide (XIV) is then oxidized with mCPBA to afford sulfoxide (XV) as a mixture of diastereoisomers. Pummerer rearrangement of sulfoxides (XV) in boiling Ac2O, followed by alkaline hydrolysis of the intermediate alpha-acetoxy sulfides furnishes aldehyde (XVI). Then, aldol condensation of aldehyde (XVI) with thiolactam (I) employing stannous triflate and N-ethylpiperidine gives adduct (XVII). Dehydration of alcohol (XVII) to the alpha,beta-unsaturated thiolactam (XVIII) is accomplished by tosylation with p-toluenesulfonic anhydride, followed by tosylate elimination in the presence of DBU. Desulfuration of thiolactam (XVIII) with deactivated Ra-Ni leads to (XIX). Then, hydrogenation of olefin (XIX) produces a mixture of epimers, from which the target isomer (X) can be isolated by column chromatography (7).

参考文献 中间体
【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
(I) 63624 methyl 3-thioxo-2,3,6,11-tetrahydro-1H-indolizino[8,7-b]indole-11b(5H)-carboxylate C16H16N2O2S 详情 详情
(VII) 63630 1-(methyloxy)-1-cyclohexene; 1-cyclohexen-1-yl methyl ether C7H12O 详情 详情
(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
(XI) 63603 2-ethyl-2-propen-1-ol C5H10O 详情 详情
(XII) 63604 (2-ethyl-2-oxiranyl)methanol C5H10O2 详情 详情
(XIII) 63634 2-[(phenylsulfanyl)methyl]-1,2-butanediol C11H16O2S 详情 详情
(XIV) 63635 2-ethyl-2-[(phenylsulfanyl)methyl]-1,4-dioxaspiro[4.5]decane; (2-ethyl-1,4-dioxaspiro[4.5]dec-2-yl)methyl phenyl sulfide C17H24O2S 详情 详情
(XV) 63636 (2-ethyl-1,4-dioxaspiro[4.5]dec-2-yl)methyl phenyl sulfoxide; 2-ethyl-2-[(phenylsulfinyl)methyl]-1,4-dioxaspiro[4.5]decane C17H24O3S 详情 详情
(XVI) 63637 　 C11H18O3 详情 详情
(XVII) 63638 methyl 2-[(2-ethyl-1,4-dioxaspiro[4.5]dec-2-yl)(hydroxy)methyl]-3-thioxo-2,3,6,11-tetrahydro-1H-indolizino[8,7-b]indole-11b(5H)-carboxylate C27H34N2O5S 详情 详情
(XVIII) 63639 methyl 2-[(2-ethyl-1,4-dioxaspiro[4.5]dec-2-yl)methylidene]-3-thioxo-2,3,6,11-tetrahydro-1H-indolizino[8,7-b]indole-11b(5H)-carboxylate C27H32N2O4S 详情 详情
(XIX) 63640 methyl 2-[(2-ethyl-1,4-dioxaspiro[4.5]dec-2-yl)methylidene]-2,3,6,11-tetrahydro-1H-indolizino[8,7-b]indole-11b(5H)-carboxylate C27H34N2O4 详情 详情

合成路线10

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

参考文献 中间体
【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11

A stereocontrolled total synthesis of vinblastine has been reported. 3-Ethyl-5-phenyl-4-pentenal (I) is transformed into cyanohydrin (II), which is further acetylated with Ac2O in pyridine to furnish the racemic alpha-acetoxy nitrile (III). Enzymatic hydrolysis of cyanohydrin acetate (III) leads to (S)-cyanohydrin (IV) as a mixture of diastereomers at the 4-ethyl group. Ozonolysis of (IV) produces the cyclic hemiacetal (V), which is subsequently dehydrated to the dihydrofuran (VI) employing mesyl chloride and triethylamine. The cyano group of (VI) is then reduced to the primary amine (VII) with LiAlH4 in THF. Acylation of amine (VII) with 2,4-dinitrobenzenesulfonyl chloride leads to the corresponding sulfonamide (VIII) (8).

参考文献 中间体
【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.
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) 63644 (E)-3-ethyl-5-phenyl-4-pentenal C13H16O 详情 详情
(II) 63645 (E)-4-ethyl-2-hydroxy-6-phenyl-5-hexenenitrile C14H17NO 详情 详情
(III) 63646 (E)-1-cyano-3-ethyl-5-phenyl-4-pentenyl acetate C16H19NO2 详情 详情
(IV) 63647 　 C14H17NO 详情 详情
(V) 63648 (2S)-4-ethyl-5-hydroxytetrahydro-2-furancarbonitrile C7H11NO2 详情 详情
(VI) 63757 (2S)-4-ethyl-2,3-dihydro-2-furancarbonitrile C7H9NO 详情 详情
(VII) 63758 [(2S)-4-ethyl-2,3-dihydro-2-furanyl]methanamine; [(2S)-4-ethyl-2,3-dihydro-2-furanyl]methylamine C7H13NO 详情 详情
(VIII) 63759 N-{[(2S)-4-ethyl-2,3-dihydro-2-furanyl]methyl}-2,4-dinitrobenzenesulfonamide C13H15N3O7S 详情 详情

合成路线12

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).

参考文献 中间体
【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13

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).

参考文献 中间体
【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14

4-Ethylpent-4-enoic acid (XXIV) is coupled to (R)-4-benzyl-2-oxazolidinone (XXV) via its mixed anhydride with pivaloyl chloride, producing the N-acyl oxazolidinone (XXVI). Diastereoselective cyanoethylation of (XXVI) with acrylonitrile leads to (XXVII). Reduction of imide (XXVII) with NaBH4, followed by protection of the resulting alcohol with t-butyldiphenylsilyl chloride furnishes the silyl ether (XXVIII). The nitrile function of (XXVIII) is then reduced by means of DIBAL to the aldehyde (XXIX), which is further treated with hydroxylamine to yield the corresponding oxime (XXX). Exposure of oxime (XXX) to NaOCl generates an intermediate nitrile oxide, which undergoes intramolecular 1,3-dipolar cycloaddition to the isoxazoline (XXXI). Subsequent reductive cleavage of the isoxazoline (XXXI) N-O bond with Zn/AcOH leads to compound (XXXII). Cyclohexanone (XXXII) is then converted to lactone (XXXIII) under Baeyer-Villiger conditions. Further methanolysis of lactone (XXXIII) gives rise to the open-chain dihydroxyester (XXXIV). Sequential protection of the primary hydroxyl group with triethylchlorosilane and the tertiary hydroxyl with trimethylchlorosilane furnishes the fully silylated triol (XXXV) (8). The lithium enolate of ester (XXXV) is then condensed with isothiocyanate (XXXVI) to produce thioanilide (XXXVII) (8, 9).

参考文献 中间体
【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
(XXV) 63776 4-ethyl-4-pentenoic acid C7H12O2 详情 详情
(XXVI) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(XXVII) 63777 (4R)-4-benzyl-3-(4-ethyl-4-pentenoyl)-1,3-oxazolidin-2-one C17H21NO3 详情 详情
(XXVIII) 63778 (4R)-4-{[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}-6-ethyl-6-heptenenitrile C20H24N2O3 详情 详情
(XXIX) 63780 (4R)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-ethyl-6-heptenenitrile C26H35NOSi 详情 详情
(XXX) 63779 (4R)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-ethyl-6-heptenal C26H36O2Si 详情 详情
(XXXI) 63781 (4R)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-ethyl-6-heptenal oxime C26H37NO2Si 详情 详情
(XXXII) 63782 (3aR,5R)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3a-ethyl-3,3a,4,5,6,7-hexahydro-2,1-benzisoxazole; [(3aR,5R)-3a-ethyl-3,3a,4,5,6,7-hexahydro-2,1-benzisoxazol-5-yl]methyl tert-butyl(diphenyl)silyl ether C26H35NO2Si 详情 详情
(XXXIII) 63783 (2S,4R)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-ethyl-2-(hydroxymethyl)cyclohexanone C26H36O3Si 详情 详情
(XXXIV) 63784 (5R,7S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-7-ethyl-7-(hydroxymethyl)-2-oxepanone C26H36O4Si 详情 详情
(XXXV) 63785 methyl (4R,6S)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-hydroxy-6-(hydroxymethyl)octanoate C27H40O5Si 详情 详情
(XXXVI) 63788 methyl (4R,6S)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-{[(triethylsilyl)oxy]methyl}-6-[(trimethylsilyl)oxy]octanoate C36H62O5Si3 详情 详情
(XXXVII) 63789 2-[(Z)-3-(tetrahydro-2H-pyran-2-yloxy)-1-propenyl]phenyl isothiocyanate; 2-{[(Z)-3-(2-isothiocyanatophenyl)-2-propenyl]oxy}tetrahydro-2H-pyran C15H17NO2S 详情 详情
(XXXVIII) 63790 methyl (4R,6S)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-({2-[(Z)-3-(tetrahydro-2H-pyran-2-yloxy)-1-propenyl]anilino}carbothioyl)-6-{[(triethylsilyl)oxy]methyl}-6-[(trimethylsilyl)oxy]octanoate C51H79NO7SSi3 详情 详情

合成路线15

Radical cyclization of thioanilide (XXXVII) gives rise to indole (XXXVIII), which is further protected as the N-Boc derivative (XXXIX) employing Boc2O. The fully protected tr (XXXIX) is then treated with 95% AcOH to furnish triol (XL). Upon treatment of triol (XL) with tosyl chloride and triethylamine in the presence of dibutyltin oxide, tosylation occurs selectively at the primary alcohol of the 1,2-diol moiety. The resulting tosylate (XLI) is further cyclized to epoxide (XLII) in the presence of NaHCO3 in hot DMF. The remaining primary alcohol of (XLIII) is then coupled to p-nitrobenzenesulfonamide (XLIII) under Mitsunobu conditions, producing (XLIV). Macrocyclization of the epoxy sulfonamide (XLIV) upon heating with K2CO3 in DMF yields the 11-membered ring compound (XLV) (8,9).

参考文献 中间体
【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
(XXXVIII) 63790 methyl (4R,6S)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-({2-[(Z)-3-(tetrahydro-2H-pyran-2-yloxy)-1-propenyl]anilino}carbothioyl)-6-{[(triethylsilyl)oxy]methyl}-6-[(trimethylsilyl)oxy]octanoate C51H79NO7SSi3 详情 详情
(XXXIX) 63810 methyl (4R,6S)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-{3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-indol-2-yl}-6-{[(triethylsilyl)oxy]methyl}-6-[(trimethylsilyl)oxy]octanoate C51H79NO7Si3 详情 详情
(XL) 63811 tert-butyl 2-{(3R,5S)-3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-1-(methoxycarbonyl)-5-{[(triethylsilyl)oxy]methyl}-5-[(trimethylsilyl)oxy]heptyl}-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-indole-1-carboxylate C56H87NO9Si3 详情 详情
(XLI) 63812 tert-butyl 2-[(3R,5S)-3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-hydroxy-5-(hydroxymethyl)-1-(methoxycarbonyl)heptyl]-3-(2-hydroxyethyl)-1H-indole-1-carboxylate C42H57NO8Si 详情 详情
(XLII) 63813 tert-butyl 2-[(3R,5S)-3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-hydroxy-1-(methoxycarbonyl)-5-({[(4-methylphenyl)sulfonyl]oxy}methyl)heptyl]-3-(2-hydroxyethyl)-1H-indole-1-carboxylate C49H63NO10SSi 详情 详情
(XLIII) 63814 tert-butyl 2-[(3R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-{[(2S)-2-ethyloxiranyl]methyl}-1-(methoxycarbonyl)butyl]-3-(2-hydroxyethyl)-1H-indole-1-carboxylate C42H55NO7Si 详情 详情
(XLIV) 55807 4-Nitrobenzenesulfonamide; p-Nitrobenzenesulfonamide 6325-93-5 C6H6N2O4S 详情 详情
(XLV) 63815 tert-butyl 2-[(3R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-{[(2S)-2-ethyloxiranyl]methyl}-1-(methoxycarbonyl)butyl]-3-(2-{[(4-nitrophenyl)sulfonyl]amino}ethyl)-1H-indole-1-carboxylate C48H59N3O10SSi 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

合成路线16

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).

参考文献 中间体
【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

合成路线17

The trifluoroacetate ester group of (L) is deprotected by treatment with triethylamine in MeOH to give (LI). Subsequent deprotection of the N-sulfonyl group with mercaptoethanol and DBU liberates the secondary amine which finally undergoes cyclization to the title compound upon intramolecular displacement of the tosylate group (8, 9).

参考文献 中间体
【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
(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
(LII) 63858 methyl (3aR,4R,5S,5aR,10bR,13aR)-4-(acetyloxy)-3a-ethyl-9-{(5S,7R,9S)-5-ethyl-5-hydroxy-9-(methoxycarbonyl)-7-({[(4-methylphenyl)sulfonyl]oxy}methyl)-3-[(4-nitrophenyl)sulfonyl]-1,2,3,4,5,6,7,8,9,10-decahydroazacycloundecino[5,4-b]indol-9-yl}-5-hydr; ethyl 2-[3-{[(1S)-2-({4-[2-(aminomethyl)-4-chlorophenoxy]butyl}amino)-1-benzylethyl]amino}-6-chloro-2-oxo-1(2H)-pyrazinyl]acetate C59H69N5O16S2 详情 详情
Extended Information