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【结 构 式】 
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【分子编号】36459 【品名】allyl (1R,2S,13R,15R,16S)-5-(allyloxy)-15-cyano-20,22-dihydroxy-13-(hydroxymethyl)-21-methoxy-6-methyl-8,10-dioxa-14,24-diazahexacyclo[14.7.1.0(2,14).0(4,12).0(7,11).0(18,23)]tetracosa-4,6,11,18,20,22-hexaene-24-carboxylate 【CA登记号】 |
【 分 子 式 】C31H33N3O9 【 分 子 量 】591.61784 【元素组成】C 62.94% H 5.62% N 7.1% O 24.34% |
合成路线1
该中间体在本合成路线中的序号：(XI)The condensation of benzaldehyde (I) with malonic ester (II) by means of piperidine and acetic acid in benzene gives the unsaturated malonate (III), which by a selective ester cleavage and a Curtius rearrangement by means of N3-PO(OPh)2 and Et3N in toluene yields the unsaturated aminoester (IV). The reduction of (IV) with a chiral rhodium catalyst affords the chiral protected aminoester (V), which is cyclized to the bridged lactone (VI) by means of BF3 ethearate in dichloromethane. Reductive cleavage of the benzyloxycarbonyl benzyl ether groups of (VI) with H2 over Pd/C affords the free aminophenol (VII). The condensation of (VII) with aldehyde (VIII) (obtained by reduction of ester (IX) with DIBAL in dichloromethane) by means of KCN and AcOH, and after allylation of the aromatic OH group with allyl bromide, the intermediate (X) is obtained. The reduction of the lactone group of (X) with DIBAL, followed by desilylation with KF and cyclization with CH3SO3H affords the polycyclic compound (XI).
| 【1】 Gin, D.Y.; Corey, E.J.; Kania, R.S.; Enantioselective total synthesis of Ecteinascidin 743. J Am Chem Soc 1996, 118, 38, 9202-03. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 | |
| (I) | 36449 | 6-(benzyloxy)-7-methyl-1,3-benzodioxole-5-carbaldehyde | C16H14O4 | 详情 | 详情 | |
| (II) | 36450 | 1-(2,2-dimethoxyethyl) 3-isobutyl malonate | C10H16O6 | 详情 | 详情 | |
| (III) | 36451 | 1-(2,2-dimethoxyethyl) 3-isobutyl 2-[(E)-[6-(benzyloxy)-7-methyl-1,3-benzodioxol-5-yl]methylidene]malonate | C26H28O9 | 详情 | 详情 | |
| (IV) | 36452 | 2,2-dimethoxyethyl (Z)-2-[[(benzyloxy)carbonyl]amino]-3-[6-(benzyloxy)-7-methyl-1,3-benzodioxol-5-yl]-2-propenoate | C30H31NO9 | 详情 | 详情 | |
| (V) | 36453 | 2,2-dimethoxyethyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[6-(benzyloxy)-7-methyl-1,3-benzodioxol-5-yl]propanoate | C30H33NO9 | 详情 | 详情 | |
| (VI) | 35454 | 2-phenyl-1H-imidazole-4-carbaldehyde | C10H8N2O | 详情 | 详情 | |
| (VII) | 36455 | (1R,12S)-9-hydroxy-8-methyl-4,6,14-trioxa-16-azatetracyclo[10.3.1.0(2,10).0(3,7)]hexadeca-2,7,9-trien-13-one | C13H13NO5 | 详情 | 详情 | |
| (VIII) | 36456 | allyl (1S)-1-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxybenzyl)-2-oxoethylcarbamate | C26H45NO6Si2 | 详情 | 详情 | |
| (IX) | 36457 | methyl (2S)-2-[[(allyloxy)carbonyl]amino]-3-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxyphenyl)propanoate | C27H47NO7Si2 | 详情 | 详情 | |
| (X) | 36458 | allyl (1S,2R)-2-[(1R,12S)-9-(allyloxy)-8-methyl-13-oxo-4,6,14-trioxa-16-azatetracyclo[10.3.1.0(2,10).0(3,7)]hexadeca-2,7,9-trien-16-yl]-1-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxybenzyl)-2-cyanoethylcarbamate | C43H61N3O10Si2 | 详情 | 详情 | |
| (XI) | 36459 | allyl (1R,2S,13R,15R,16S)-5-(allyloxy)-15-cyano-20,22-dihydroxy-13-(hydroxymethyl)-21-methoxy-6-methyl-8,10-dioxa-14,24-diazahexacyclo[14.7.1.0(2,14).0(4,12).0(7,11).0(18,23)]tetracosa-4,6,11,18,20,22-hexaene-24-carboxylate | C31H33N3O9 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)The selective trifluoromethanesulfonation of the least hindered phenolic OH group of (XI) with Tf2NPh, TEA and DMAP gives monosulfonate (XII), which is selectively silylated at the primary OH group with TBDPSCl yielding silyl ether (XIII). The protection of the last OH group of (XIII) with Mom-Br and DIEA affords the fully protected intermediate (XIV), which is deallylated with Bu3SnH and PdCl2(PPh3)2 to give the intermediate (XV). The reductive methylation of the NH group of (XV) with formaldehyde and NaBH3CN yields the N-methyl derivative (XVI). The replacement of the CF3SO3 group of (XVI) by methyl is performed by treatment with Me4Sn and PdCl2(PPh3)2 in hot DMF provides the phenol (XVII), which is oxidized with (PhSeO)2O and desilylated with TBAF to give the dihydroxydienone (XVIII).
| 【1】 Gin, D.Y.; Corey, E.J.; Kania, R.S.; Enantioselective total synthesis of Ecteinascidin 743. J Am Chem Soc 1996, 118, 38, 9202-03. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 36459 | allyl (1R,2S,13R,15R,16S)-5-(allyloxy)-15-cyano-20,22-dihydroxy-13-(hydroxymethyl)-21-methoxy-6-methyl-8,10-dioxa-14,24-diazahexacyclo[14.7.1.0(2,14).0(4,12).0(7,11).0(18,23)]tetracosa-4,6,11,18,20,22-hexaene-24-carboxylate | C31H33N3O9 | 详情 | 详情 | |
| (XII) | 36460 | allyl (1R,2S,13R,15R,16S)-5-(allyloxy)-15-cyano-22-hydroxy-13-(hydroxymethyl)-21-methoxy-6-methyl-20-[[(trifluoromethyl)sulfonyl]oxy]-8,10-dioxa-14,24-diazahexacyclo[14.7.1.0(2,14).0(4,12).0(7,11).0(18,23)]tetracosa-4,6,11,18,20,22-hexaene-24-carbox | C32H32F3N3O11S | 详情 | 详情 | |
| (XIII) | 36461 | allyl (1R,2S,13R,15R,16S)-5-(allyloxy)-13-([[tert-butyl(diphenyl)silyl]oxy]methyl)-15-cyano-22-hydroxy-21-methoxy-6-methyl-20-[[(trifluoromethyl)sulfonyl]oxy]-8,10-dioxa-14,24-diazahexacyclo[14.7.1.0(2,14).0(4,12).0(7,11).0(18,23)]tetracosa-4,6,11,1 | C48H50F3N3O11SSi | 详情 | 详情 | |
| (XIV) | 36462 | allyl (1R,2S,13R,15R,16S)-5-(allyloxy)-13-([[tert-butyl(diphenyl)silyl]oxy]methyl)-15-cyano-21-methoxy-22-(methoxymethoxy)-6-methyl-20-[[(trifluoromethyl)sulfonyl]oxy]-8,10-dioxa-14,24-diazahexacyclo[14.7.1.0(2,14).0(4,12).0(7,11).0(18,23)]tetracosa | C50H54F3N3O12SSi | 详情 | 详情 | |
| (XV) | 36463 | (1R,2S,13R,15R,16S)-13-([[tert-butyl(diphenyl)silyl]oxy]methyl)-15-cyano-5-hydroxy-21-methoxy-22-(methoxymethoxy)-6-methyl-8,10-dioxa-14,24-diazahexacyclo[14.7.1.0(2,14).0(4,12).0(7,11).0(18,23)]tetracosa-4,6,11,18,20,22-hexaen-20-yl trifluoromethan | C43H46F3N3O10SSi | 详情 | 详情 | |
| (XVI) | 36464 | (1R,2S,13R,15R,16S)-13-([[tert-butyl(diphenyl)silyl]oxy]methyl)-15-cyano-5-hydroxy-21-methoxy-22-(methoxymethoxy)-6,24-dimethyl-8,10-dioxa-14,24-diazahexacyclo[14.7.1.0(2,14).0(4,12).0(7,11).0(18,23)]tetracosa-4,6,11,18,20,22-hexaen-20-yl trifluorom | C44H48F3N3O10SSi | 详情 | 详情 | |
| (XVII) | 36465 | (1R,2S,13R,15R,16S)-13-([[tert-butyl(diphenyl)silyl]oxy]methyl)-5-hydroxy-21-methoxy-22-(methoxymethoxy)-6,20,24-trimethyl-8,10-dioxa-14,24-diazahexacyclo[14.7.1.0(2,14).0(4,12).0(7,11).0(18,23)]tetracosa-4,6,11,18,20,22-hexaene-15-carbonitrile | C44H51N3O7Si | 详情 | 详情 | |
| (XVIII) | 36466 | (1R,2S,4R,13R,15R,16S)-4-hydroxy-13-(hydroxymethyl)-21-methoxy-22-(methoxymethoxy)-6,20,24-trimethyl-5-oxo-8,10-dioxa-14,24-diazahexacyclo[14.7.1.0(2,14).0(4,12).0(7,11).0(18,23)]tetracosa-6,11,18,20,22-pentaene-15-carbonitrile | C28H33N3O8 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XI)The previously reported synthesis of 139221 (scheme 13922101a) has been investigated in order to find a more efficient, reproducible and economical route to work in the mutikilogram scale. Herein it is reported a new process which is simpler and proceeds with an overall yield of 54% (the original process, 35%). The condensation of intermediate aminolactone (I) (scheme 13922101a, intermediate (VII)) with acid (XLII) (the acid derived from scheme 13922101a, intermediate ester (IX)) by means of 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP), and 1-hydroxy-7-azabenzotriazole (HOAt) in THF/dichloromethane gives the coupling product (XLIII), which is allylated with allyl bromide (XLIV) and Cs2CO3 in DMF yielding the allyl ether (XLV). The reduction of the lactone group of (XLV) with LiAlH2(OEt)2 in ethyl ether affords the lactol (XLVI), which is desilylated with KF in methanol to provide the phenolic compound (XLVII). The opening of the lactol ring of (XLVII) with simultaneous cyclization by means of Tf-OH in water/trifluoroethanol gives the hexacyclic intermediate (XLVIII), which is finally reductocondensed with KCN by means of LiAlH2(OEt)2 in THF to furnish the previously reported pentacyclic intermediate (XI) (scheme 13922101a, intermediate (XI)).
| 【1】 Martinez, E.J.; Corey, E.J.; A new, more efficient, and effective process for the synthesis of a key pentacyclic intermediate for production of ecteinascidin and phthalascidin antitumor agents. Org Lett 2000, 2, 7, 993. |
| 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) | 36455 | (1R,12S)-9-hydroxy-8-methyl-4,6,14-trioxa-16-azatetracyclo[10.3.1.0(2,10).0(3,7)]hexadeca-2,7,9-trien-13-one | C13H13NO5 | 详情 | 详情 | |
| (XI) | 36459 | allyl (1R,2S,13R,15R,16S)-5-(allyloxy)-15-cyano-20,22-dihydroxy-13-(hydroxymethyl)-21-methoxy-6-methyl-8,10-dioxa-14,24-diazahexacyclo[14.7.1.0(2,14).0(4,12).0(7,11).0(18,23)]tetracosa-4,6,11,18,20,22-hexaene-24-carboxylate | C31H33N3O9 | 详情 | 详情 | |
| (XLII) | 38116 | (2S)-2-[[(allyloxy)carbonyl]amino]-3-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxyphenyl)propionic acid | C26H45NO7Si2 | 详情 | 详情 | |
| (XLIII) | 38117 | allyl (1S)-1-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxybenzyl)-2-[(1R,12S)-9-hydroxy-8-methyl-13-oxo-4,6,14-trioxa-16-azatetracyclo[10.3.1.0(2,10).0(3,7)]hexadeca-2,7,9-trien-16-yl]-2-oxoethylcarbamate | C39H56N2O11Si2 | 详情 | 详情 | |
| (XLIV) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (XLV) | 38118 | allyl (1S)-2-[(1R,12S)-9-(allyloxy)-8-methyl-13-oxo-4,6,14-trioxa-16-azatetracyclo[10.3.1.0(2,10).0(3,7)]hexadeca-2,7,9-trien-16-yl]-1-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxybenzyl)-2-oxoethylcarbamate | C42H60N2O11Si2 | 详情 | 详情 | |
| (XLVI) | 38119 | allyl (1S)-2-[(1R,12S,13S)-9-(allyloxy)-13-hydroxy-8-methyl-4,6,14-trioxa-16-azatetracyclo[10.3.1.0(2,10).0(3,7)]hexadeca-2,7,9-trien-16-yl]-1-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxybenzyl)-2-oxoethylcarbamate | C42H62N2O11Si2 | 详情 | 详情 | |
| (XLVII) | 38120 | allyl (1S)-2-[(1R,12S,13S)-9-(allyloxy)-13-hydroxy-8-methyl-4,6,14-trioxa-16-azatetracyclo[10.3.1.0(2,10).0(3,7)]hexadeca-2,7,9-trien-16-yl]-1-(3,5-dihydroxy-4-methoxybenzyl)-2-oxoethylcarbamate | C30H34N2O11 | 详情 | 详情 | |
| (XLVIII) | 38121 | allyl (1R,2S,13R,16S)-5-(allyloxy)-20,22-dihydroxy-13-(hydroxymethyl)-21-methoxy-6-methyl-15-oxo-8,10-dioxa-14,24-diazahexacyclo[14.7.1.0(2,14).0(4,12).0(7,11).0(18,23)]tetracosa-4,6,11,18,20,22-hexaene-24-carboxylate | C30H32N2O10 | 详情 | 详情 |