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【结 构 式】

【药物名称】Trabectedin, Ecteinascidin 743, NSC-684766, ET-743, Yondelis

【化学名称】(1'R,6R,6aR,7R,13S,14S,16R)-5-Acetoxy-6',8,14-trihydroxy-7',9-dimethoxy-4,10,23-trimethyl-1',2',3',4',6a,7,12,13,14,16-decahydro-6H-spiro[6,16-(epithiopropanoxymethano)-7,13-imino-1,3-dioxolo[7,8]isoquino[3,2-b][3]benzazocine-20,1'-isoquinolin]-19-one

【CA登记号】114899-77-3

【 分 子 式 】C39H43N3O11S

【 分 子 量 】761.85506

【开发单位】PharmaMar (Orphan Drug), University of Illinois (Originator), Ortho Biotech (Licensee), PharmaMar (Licensee), Zeltia (Licensee)

【药理作用】Breast Cancer Therapy, Lung Cancer Therapy, Non-Small Cell Lung Cancer Therapy, Oncolytic Drugs, Ovarian Cancer Therapy, Prostate Cancer Therapy, Solid Tumors Therapy, Apoptosis Inducers, DNA-Intercalating Drugs

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 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).

参考文献 中间体
【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

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).

参考文献 中间体
【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

The esterification of the primary OH group of (XVIII) with the protected cysteine (XIX) by means of EDC and DMAP in dichloromethane gives ester (XX), which is cyclized by means of trifluoromethanesulfonic anhydride and DMSO yielding the bridged lactone (XXI). The oxidation of (XXI) with N-methylpyridinium-4-carbaldehyde (NMPA), DBU and PdCl2(PPh3)2 affords the oxolactone (XXII), which is finally cyclized with 2-(3-hydroxy-4-methoxyphenyl)ethylamine (XXIII) by means of TFA and AgNO3 in water.

参考文献 中间体
【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
(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
(XIX) 36467 (2R)-2-[[(allyloxy)carbonyl]amino]-3-[(9H-fluoren-9-ylmethyl)sulfanyl]propionic acid C21H21NO4S 详情 详情
(XX) 36468 　 C49H52N4O11S 详情 详情
(XXI) 36469 (1R,2R,3R,11S,12R,14R)-26-[[(allyloxy)carbonyl]amino]-12-cyano-6-methoxy-5-(methoxymethoxy)-7,21,30-trimethyl-27-oxo-17,19,28-trioxa-24-thia-13,30-diazaheptacyclo[12.9.6.1(3,11).0(2,13).0(4,9).0(15,23).0(16,20)]triaconta-4,6,8,15,20,22-hexaen-22-yl C37H42N4O11S 详情 详情
(XXII) 36470 (1R,2R,3R,11S,12R,14R)-12-cyano-6-methoxy-5-(methoxymethoxy)-7,21,30-trimethyl-26,27-dioxo-17,19,28-trioxa-24-thia-13,30-diazaheptacyclo[12.9.6.1(3,11).0(2,13).0(4,9).0(15,23).0(16,20)]triaconta-4,6,8,15,20,22-hexaen-22-yl acetate C33H35N3O10S 详情 详情
(XXIII) 36471 5-(2-aminoethyl)-2-methoxyphenol C9H13NO2 详情 详情

合成路线4

6-(Benzyloxy)-7-methyl-1,3-benzodioxole-5-carbaldehyde (scheme 13922101a, cp. (I)). The protection of the OH group of phenol (XXIV) with Mom-Br and NaH in DMF/ethyl ether gives the methoxymethyl ether (XXV), which is methylated with MeI and BuLi in hexane yielding the 4-methyl derivative (XXVI). The formylation of (XXVI) with n-BuLi and DMF in THF affords the carbaldehyde (XXVII), which is deprotected with MsOH in dichloromethane giving 6-hydroxy-7-methyl-1,3-benzodioxole-5-carbaldehyde (XXVIII). Finally, this compound is benzylated with benzyl bromide and NaH in DMF providing the desired intermediate (I).

参考文献 中间体
【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
(I) 36449 6-(benzyloxy)-7-methyl-1,3-benzodioxole-5-carbaldehyde C16H14O4 详情 详情
(XXIV) 10985 1,3-Benzodioxol-5-ol; Sesamol 533-31-3 C7H6O3 详情 详情
(XXV) 38101 1,3-benzodioxol-5-yl methoxymethyl ether; 5-(methoxymethoxy)-1,3-benzodioxole C9H10O4 详情 详情
(XXVI) 38102 5-(methoxymethoxy)-4-methyl-1,3-benzodioxole; methoxymethyl 4-methyl-1,3-benzodioxol-5-yl ether C10H12O4 详情 详情
(XXVII) 38103 6-(methoxymethoxy)-7-methyl-1,3-benzodioxole-5-carbaldehyde C11H12O5 详情 详情
(XXVIII) 38104 6-hydroxy-7-methyl-1,3-benzodioxole-5-carbaldehyde C9H8O4 详情 详情

合成路线5

Malonic acid allyl, 2,2-dimethoxyethyl diester (scheme 13922101a, cp. (II)). The reaction of allyl acetate (XXIX) with LDA and CO2 in ethyl ether gives the malonic acid monoallyl ester (XXX), which is then esterified with 2,2-dimethoxyethanol (XXXI) by means of BOP-Cl and TEA in dichloromethane to afford the desired intermediate (II).

参考文献 中间体
【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
(II) 36450 1-(2,2-dimethoxyethyl) 3-isobutyl malonate C10H16O6 详情 详情
(XXIX) 27147 allyl acetate 591-87-7 C5H8O2 详情 详情
(XXX) 38105 3-(allyloxy)-3-oxopropionic acid C6H8O4 详情 详情
(XXXI) 38106 2,2-dimethoxy-1-ethanol 30934-97-5 C4H10O3 详情 详情

合成路线6

(S)-2-(Allyloxycarbonylamino)-3-[4-methoxy-3,5-bis(tert-butyldimethylsilyloxy)phenyl]propionic acid methyl ester (scheme 13922101a, cp. (IX)). The silylation of 3,5-dihydroxy-4-methoxybenzoic acid methyl ester (XXXII) with TBDMS-Cl, TEA and DMAP in dichloromethane gives the silylated compound (XXXIII), which is reduced with DIBAL in dichloromethane yielding the corresponding benzyl alcohol (XXXIV). The oxidation of (XXXIV) with pyridinium dichromate (PDC) in dichloromethane affords the benzaldehyde (XXXV), which is condensed with malonic acid monomethyl ester (XXXVI) by means of piperidine/AcOH in toluene providing the corresponding benzylidene derivative (XXXVII). The reaction of (XXXVII) with (PhO)2PO-N3 and benzyl alcohol in hot toluene affords the benzyloxycarbonylamino derivative (XXXVIII), which is enantioselectively reduced with H2 over a chiral Rh catalyst in methanol providing and (S)-2-(benzyloxycarbonylamino)-3-[4-methoxy-3,5-bis(tert-butyldimethylsilyloxy)phenyl]propionic acid methyl ester (XXXIX). Elimination of the benzyl protecting group of (XXXIX) with H2 over Pd/C in ethyl acetate gives the free aminoester (XL), which is finally reprotected with allyl chloroformate (XLI) and pyridine to furnish the desired intermediate (IX).

参考文献 中间体
【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
(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
(XXXII) 38107 methyl 3,5-dihydroxy-4-methoxybenzoate C9H10O5 详情 详情
(XXXIII) 38108 methyl 3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxybenzoate C21H38O5Si2 详情 详情
(XXXIV) 38109 (3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxyphenyl)methanol C20H38O4Si2 详情 详情
(XXXV) 38110 3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxybenzaldehyde C20H36O4Si2 详情 详情
(XXXVI) 16198 3-Methoxy-3-oxopropionic acid; Malonic acid monomethyl ester 16695-14-0 C4H6O4 详情 详情
(XXXVII) 38111 (E)-3-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxyphenyl)-2-(methoxycarbonyl)-2-propenoic acid C24H40O7Si2 详情 详情
(XXXVIII) 38112 methyl (Z)-2-[[(benzyloxy)carbonyl]amino]-3-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxyphenyl)-2-propenoate C31H47NO7Si2 详情 详情
(XXXIX) 38113 methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxyphenyl)propanoate C31H49NO7Si2 详情 详情
(XL) 38114 methyl (2S)-2-amino-3-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxyphenyl)propanoate C23H43NO5Si2 详情 详情
(XLI) 38115 3-[(chlorocarbonyl)oxy]-1-propene 2937-50-0 C4H5ClO2 详情 详情

合成路线7

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)).

参考文献 中间体
【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

合成路线8

Reaction of cyanosafracin B (I) with Boc2O in ethanol gives the amino-protected compound (II), which is treated with methoxymethyl bromide (MOM-Br), DIEA and DMAP in acetonitrile yielding the O-protected compound (III). The demethylation of (III) with NaOH in methanol affords the hydroxyquinone (IV), which is reduced with H2 over Pd/C and cyclized with bromochloromethane and Cs2CO3 in hot DMF to provide compound (V). Reaction of (V) with allyl bromide (VI) and Cs2CO3 in DMF gives the allyl ether (VII), which first is treated with TFA, phenyl isothiocyanate and HCl to yield the primary amine (VIII) and then protected at the free NH2 group with Troc-Cl and pyridine, to afford the amino protected compound (IX).

参考文献 中间体
【1】 Cuevas, C.; Martin, M.J.; Perez, M.; et al.; Synthesis of ecteinascidin ET-743 and phathalascidin Pt-650 from cyanosafracin B. Org Lett 2000, 2, 16, 2545.
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) 41775 (2S)-2-amino-N-[[(1S,2S,10R,12R,13R)-12-cyano-19-hydroxy-7,18-dimethoxy-6,17,21-trimethyl-5,8-dioxo-11,21-diazapentacyclo[11.7.1.0(2,11).0(4,9).0(15,20)]henicosa-4(9),6,15,17,19-pentaen-10-yl]methyl]propanamide C29H35N5O6 详情 详情
(II) 41776 tert-butyl (1S)-2-([[(1S,2S,10R,12R,13R)-12-cyano-19-hydroxy-7,18-dimethoxy-6,17,21-trimethyl-5,8-dioxo-11,21-diazapentacyclo[11.7.1.0(2,11).0(4,9).0(15,20)]henicosa-4(9),6,15,17,19-pentaen-10-yl]methyl]amino)-1-methyl-2-oxoethylcarbamate C34H43N5O8 详情 详情
(III) 41777 tert-butyl (1S)-2-([[(1S,2S,10R,12R,13R)-12-cyano-7,18-dimethoxy-19-(methoxymethoxy)-6,17,21-trimethyl-5,8-dioxo-11,21-diazapentacyclo[11.7.1.0(2,11).0(4,9).0(15,20)]henicosa-4(9),6,15,17,19-pentaen-10-yl]methyl]amino)-1-methyl-2-oxoethylcarbamate C36H47N5O9 详情 详情
(IV) 41778 tert-butyl (1S)-2-([[(1S,2S,10R,12R,13R)-12-cyano-7-hydroxy-18-methoxy-19-(methoxymethoxy)-6,17,21-trimethyl-5,8-dioxo-11,21-diazapentacyclo[11.7.1.0(2,11).0(4,9).0(15,20)]henicosa-4(9),6,15,17,19-pentaen-10-yl]methyl]amino)-1-methyl-2-oxoethylcarba C35H45N5O9 详情 详情
(V) 41779 tert-butyl (1S)-2-([[(1S,2S,13R,15R,16R)-15-cyano-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-hexaen-13-yl]methyl]amino)-1-methyl-2-oxoe C36H47N5O9 详情 详情
(VI) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(VII) 41780 tert-butyl (1S)-2-([[(1S,2S,13R,15R,16R)-5-(allyloxy)-15-cyano-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-hexaen-13-yl]methyl]amino)-1-methyl-2-o C39H51N5O9 详情 详情
(VIII) 41781 (1S,2S,13R,15R,16R)-5-(allyloxy)-13-(aminomethyl)-22-hydroxy-21-methoxy-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 C29H34N4O5 详情 详情
(IX) 41782 2,2,2-trichloroethyl [(1S,2S,13R,15R,16R)-5-(allyloxy)-15-cyano-22-hydroxy-21-methoxy-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-hexaen-13-yl]methylcarbamate C32H35Cl3N4O7 详情 详情

合成路线9

Reaction of (IX) with MOM-Br and DIEA as before affords the ether (X), which is treated with Zn/HOAc in order to regenerate the primary amino group giving (XI). The reaction of (XI) with NaNO2 and HOAc eliminates the NH2 group, affording the primary alcohol (XII), which is esterified with the protected (S)-cysteine (XIII) by means of EDC and DMAP in dichloromethane furnishing the cysteine ester (XIV). Reaction of (XIV) with Bu3SnH and PdCl2(PPh3)2, followed by oxidation with (PhSeO)2O in dichloromethane gives the hydroxyketone (XV), which is cyclized with Tf2O and Ac2O yielding the heptacyclic compound (XVI). Elimination of the MOM protecting group with TMSCl and NaI in CH3CN/CH2Cl2 affords the phenolic compound (XVII).

参考文献 中间体
【1】 Cuevas, C.; Martin, M.J.; Perez, M.; et al.; Synthesis of ecteinascidin ET-743 and phathalascidin Pt-650 from cyanosafracin B. Org Lett 2000, 2, 16, 2545.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IX) 41782 2,2,2-trichloroethyl [(1S,2S,13R,15R,16R)-5-(allyloxy)-15-cyano-22-hydroxy-21-methoxy-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-hexaen-13-yl]methylcarbamate C32H35Cl3N4O7 详情 详情
(X) 41783 2,2,2-trichloroethyl [(1S,2S,13R,15R,16R)-5-(allyloxy)-15-cyano-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-hexaen-13-yl]methylcarbamate C34H39Cl3N4O8 详情 详情
(XI) 41784 (1S,2S,13R,15R,16R)-5-(allyloxy)-13-(aminomethyl)-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 C31H38N4O6 详情 详情
(XII) 41785 (1S,2S,13R,15R,16R)-5-(allyloxy)-13-(hydroxymethyl)-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 C31H37N3O7 详情 详情
(XIII) 41786 (2S)-3-[(9H-fluoren-9-ylmethyl)sulfanyl]-2-[[(2,2,2-trichloroethoxy)carbonyl]amino]propionic acid C20H18Cl3NO4S 详情 详情
(XIV) 41787 [(1S,2S,13R,15R,16R)-5-(allyloxy)-15-cyano-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-hexaen-13-yl]methyl (2S)-3-[(9H-fluoren-9-ylmethyl)sulfanyl C51H53Cl3N4O10S 详情 详情
(XV) 41788 　 C48H49Cl3N4O11S 详情 详情
(XVI) 41789 　 C36H39Cl3N4O11S 详情 详情
(XVII) 41790 　 C34H35Cl3N4O10S 详情 详情

合成路线10

Intermediate (XVII) by a treatment with Zn and HOAc eliminates the Troc protecting group, giving the primary amine (XVIII). This compound by treatment with 4-formyl-1-methylpyridinium iodide (NMPC), DBU and oxalic acid in order to convert the nitrile group into an alcohol, provides compund (XIX), which is finally cyclized with 2-(3-hydroxy-4-methoxyphenyl)ethylamine (XX) by means of SiO2 / EtOH, followed treatment with and AgNO3 in acetonitrile/water.

参考文献 中间体
【1】 Cuevas, C.; Martin, M.J.; Perez, M.; et al.; Synthesis of ecteinascidin ET-743 and phathalascidin Pt-650 from cyanosafracin B. Org Lett 2000, 2, 16, 2545.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVII) 41790 　 C34H35Cl3N4O10S 详情 详情
(XVIII) 41791 (1R,2R,3S,11R,12R,14R,26R)-26-amino-12-cyano-5-hydroxy-6-methoxy-7,21,30-trimethyl-27-oxo-17,19,28-trioxa-24-thia-13,30-diazaheptacyclo[12.9.6.1(3,11).0(2,13).0(4,9).0(15,23).0(16,20)]triaconta-4,6,8,15,20,22-hexaen-22-yl acetate C31H34N4O8S 详情 详情
(XIX) 41792 (1R,2R,3S,11R,12S,14R,26R)-26-amino-5,12-dihydroxy-6-methoxy-7,21,30-trimethyl-27-oxo-17,19,28-trioxa-24-thia-13,30-diazaheptacyclo[12.9.6.1(3,11).0(2,13).0(4,9).0(15,23).0(16,20)]triaconta-4,6,8,15,20,22-hexaen-22-yl acetate C30H35N3O9S 详情 详情
(XX) 36471 5-(2-aminoethyl)-2-methoxyphenol C9H13NO2 详情 详情

合成路线11

Synthesis of the amine intermediate (VIII): The condensation of 1,3-benzodioxole (I) with the didehydro morpholinone (II) by means of TFA in dichloromethane gives the chiral adduct (III), which is treated with Tf2O and pyridine in dichloromethane to yield the triflate (IV). The reductive cleavage of (IV) by means of NaBH4 in methanol affords the aminodiol (V), which is selectively monosilylated at the primary OH group with Tbdps-Cl and imidazole to provide the silyl ether (VI). The reaction of the triflate group of (VI) with MeZnCl and PdCl2(dppf) in refluxing THF gives the methylated compound (VII), which is treated with Pb(OAc)4 and NH2OH in ethanol to afford the target primary amine intermediate (VIII).

参考文献 中间体
【1】 Abe, M.; Yanagisawa, A.; Tohma, S.; Kan, T.; Fukuyama, T.; Endo, A.; Total synthesis of ecteinascidin 743. J Am Chem Soc 2002, 124, 23, 6552.
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) 58601 5-(methoxymethoxy)-1,3-benzodioxol-4-ol C9H10O5 详情 详情
(II) 58602 (5R)-6,6-dimethyl-5-phenyl-5,6-dihydro-2H-1,4-oxazin-2-one C12H13NO2 详情 详情
(III) 58603 (3R,5R)-3-[7-hydroxy-6-(methoxymethoxy)-1,3-benzodioxol-4-yl]-6,6-dimethyl-5-phenyl-2-morpholinone C21H23NO7 详情 详情
(IV) 58604 7-[(3R,5R)-6,6-dimethyl-2-oxo-5-phenylmorpholinyl]-5-(methoxymethoxy)-1,3-benzodioxol-4-yl trifluoromethanesulfonate C22H22F3NO9S 详情 详情
(V) 58605 7-((1R)-2-hydroxy-1-{[(1R)-2-hydroxy-2-methyl-1-phenylpropyl]amino}ethyl)-5-(methoxymethoxy)-1,3-benzodioxol-4-yl trifluoromethanesulfonate C22H26F3NO9S 详情 详情
(VI) 58606 7-((1R)-2-{[tert-butyl(diphenyl)silyl]oxy}-1-{[(1R)-2-hydroxy-2-methyl-1-phenylpropyl]amino}ethyl)-5-(methoxymethoxy)-1,3-benzodioxol-4-yl trifluoromethanesulfonate C38H44F3NO9SSi 详情 详情
(VII) 58607 (1R)-1-({(1R)-2-{[tert-butyl(diphenyl)silyl]oxy}-1-[6-(methoxymethoxy)-7-methyl-1,3-benzodioxol-4-yl]ethyl}amino)-2-methyl-1-phenyl-2-propanol C38H47NO6Si 详情 详情
(VIII) 58608 (1R)-2-{[tert-butyl(diphenyl)silyl]oxy}-1-[6-(methoxymethoxy)-7-methyl-1,3-benzodioxol-4-yl]-1-ethanamine; (1R)-2-{[tert-butyl(diphenyl)silyl]oxy}-1-[6-(methoxymethoxy)-7-methyl-1,3-benzodioxol-4-yl]ethylamine C28H35NO5Si 详情 详情

合成路线12

Synthesis of the iodo-L-phenylalanine intermediate (XVII): The condensation of catechol derivative (IX) with methyl orthoformate by means of BuLi and CSA in methanol gives the benzaldehyde dimethyl acetal (X), which is iodinated with I2 and BuLi in ethyl ether to yield the iodobenzaldehyde acetal (XI). The hydrolysis of the acetal group of (XI) by means of HCl in THF affords the 3-hydroxy benzaldehyde derivative (XII), which is treated with benzyl bromide and K2CO3 in refluxing acetonitrile to provide the benzyl protected benzaldehyde derivative (XIII). The Horner-Emmons condensation of aldehyde (XIII) with phosphonate (XIV) by means of TMG in dichloromethane gives the dehydrophenylalanine derivative (XV), which is submitted to an asymmetric hydrogenation with H2 over a chiral Rh catalyst in hot ethyl acetate to yield the L-enantiomer (XVI). Finally, the ester group of (XVI) is hydrolyzed with LiOH in methanol/water to afford the target iodo-L-phenylalanine intermediate (XVII).

参考文献 中间体
【1】 Abe, M.; Yanagisawa, A.; Tohma, S.; Kan, T.; Fukuyama, T.; Endo, A.; Total synthesis of ecteinascidin 743. J Am Chem Soc 2002, 124, 23, 6552.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IX) 58609 4-bromo-2-(methoxymethoxy)-6-methylphenyl methyl ether; 5-bromo-2-methoxy-1-(methoxymethoxy)-3-methylbenzene C10H13BrO3 详情 详情
(X) 58610 5-(dimethoxymethyl)-2-methoxy-1-(methoxymethoxy)-3-methylbenzene; 4-(dimethoxymethyl)-2-(methoxymethoxy)-6-methylphenyl methyl ether C13H20O5 详情 详情
(XI) 58611 1-(dimethoxymethyl)-2-iodo-4-methoxy-3-(methoxymethoxy)-5-methylbenzene; 4-(dimethoxymethyl)-3-iodo-2-(methoxymethoxy)-6-methylphenyl methyl ether C13H19IO5 详情 详情
(XII) 58612 3-hydroxy-2-iodo-4-methoxy-5-methylbenzaldehyde C9H9IO3 详情 详情
(XIII) 58613 3-(benzyloxy)-2-iodo-4-methoxy-5-methylbenzaldehyde C16H15IO3 详情 详情
(XIV) 34562 methyl 2-[(tert-butoxycarbonyl)amino]-2-(dimethoxyphosphoryl)acetate C10H20NO7P 详情 详情
(XV) 58614 methyl (Z)-3-[3-(benzyloxy)-2-iodo-4-methoxy-5-methylphenyl]-2-[(tert-butoxycarbonyl)amino]-2-propenoate C24H28INO6 详情 详情
(XVI) 58615 methyl (2S)-3-[3-(benzyloxy)-2-iodo-4-methoxy-5-methylphenyl]-2-[(tert-butoxycarbonyl)amino]propanoate C24H30INO6 详情 详情
(XVII) 58616 (2S)-3-[3-(benzyloxy)-2-iodo-4-methoxy-5-methylphenyl]-2-[(tert-butoxycarbonyl)amino]propanoic acid C23H28INO6 详情 详情

合成路线13

The condensation of the amine intermediate (VIII) with iodo-L-phenylalanine intermediate (XVII), 4-methoxyphenyl isocyanide (XVIII) and acetaldehyde (XIX) in refluxing methanol gives the adduct (XX), which is desilylated with TBAF in THF and acylated with Ac2O and pyridine to yield the acetoxy derivative (XXI). Elimination of the Mom and Boc protecting groups of (XXI) by means of TFA in dichloromethane affords the aminophenol (XXII), which is submitted to cyclization in refluxing ethyl acetate to provide the piperazinedione derivative (XXIII). The reaction of the OH group of (XXIII) with MsCl and pyridine in dichloromethane and the piperazine NH with Boc2O and DMAP in acetonitrile gives the fully protected compound (XXIV), which is reduced with NaBH4 in EtOH/dichloromethane and dehydrated by means of CSA and quinoline in refluxing toluene to yield the tetrahydropyrazinone (XXV). The cyclization of (XXV) by means of Pd2(dba)3, P(o-tol)3 and TEA in refluxing acetonitrile affords the tricyclic compound (XXVI).

参考文献 中间体
【1】 Abe, M.; Yanagisawa, A.; Tohma, S.; Kan, T.; Fukuyama, T.; Endo, A.; Total synthesis of ecteinascidin 743. J Am Chem Soc 2002, 124, 23, 6552.
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) 58608 (1R)-2-{[tert-butyl(diphenyl)silyl]oxy}-1-[6-(methoxymethoxy)-7-methyl-1,3-benzodioxol-4-yl]-1-ethanamine; (1R)-2-{[tert-butyl(diphenyl)silyl]oxy}-1-[6-(methoxymethoxy)-7-methyl-1,3-benzodioxol-4-yl]ethylamine C28H35NO5Si 详情 详情
(XVII) 58616 (2S)-3-[3-(benzyloxy)-2-iodo-4-methoxy-5-methylphenyl]-2-[(tert-butoxycarbonyl)amino]propanoic acid C23H28INO6 详情 详情
(XVIII) 58617 4-methoxy-N-methyleneaniline; N-(4-methoxyphenyl)-N-methyleneamine C8H9NO 详情 详情
(XIX) 11974 Acetaldehyde 75-07-0 C2H4O 详情 详情
(XX) 58618 tert-butyl (1S)-1-[3-(benzyloxy)-2-iodo-4-methoxy-5-methylbenzyl]-2-{{(1R)-2-{[tert-butyl(diphenyl)silyl]oxy}-1-[6-(methoxymethoxy)-7-methyl-1,3-benzodioxol-4-yl]ethyl}[2-(4-methoxyanilino)-1-methyl-2-oxoethyl]amino}-2-oxoethylcarbamate C61H72IN3O12Si 详情 详情
(XXI) 58619 (2R)-2-{{(2S)-3-[3-(benzyloxy)-2-iodo-4-methoxy-5-methylphenyl]-2-[(tert-butoxycarbonyl)amino]propanoyl}[2-(4-methoxyanilino)-1-methyl-2-oxoethyl]amino}-2-[6-(methoxymethoxy)-7-methyl-1,3-benzodioxol-4-yl]ethyl acetate C47H56IN3O13 详情 详情
(XXII) 58620 (2R)-2-{{(2S)-2-amino-3-[3-(benzyloxy)-2-iodo-4-methoxy-5-methylphenyl]propanoyl}[2-(4-methoxyanilino)-1-methyl-2-oxoethyl]amino}-2-(6-hydroxy-7-methyl-1,3-benzodioxol-4-yl)ethyl acetate C40H44IN3O10 详情 详情
(XXIII) 58621 (2R)-2-{(3S)-3-[3-(benzyloxy)-2-iodo-4-methoxy-5-methylbenzyl]-6-methyl-2,5-dioxopiperazinyl}-2-(6-hydroxy-7-methyl-1,3-benzodioxol-4-yl)ethyl acetate C33H35IN2O9 详情 详情
(XXIV) 58622 tert-butyl (2S)-4-((1R)-2-(acetyloxy)-1-{7-methyl-6-[(methylsulfonyl)oxy]-1,3-benzodioxol-4-yl}ethyl)-2-[3-(benzyloxy)-2-iodo-4-methoxy-5-methylbenzyl]-5-methyl-3,6-dioxo-1-piperazinecarboxylate C39H45IN2O13S 详情 详情
(XXV) 58623 tert-butyl (2S)-4-((1R)-2-(acetyloxy)-1-{7-methyl-6-[(methylsulfonyl)oxy]-1,3-benzodioxol-4-yl}ethyl)-2-[3-(benzyloxy)-2-iodo-4-methoxy-5-methylbenzyl]-5-methyl-3-oxo-3,4-dihydro-1(2H)-pyrazinecarboxylate C39H45IN2O12S 详情 详情
(XXVI) 58624 tert-butyl (1R,9S)-11-((1R)-2-(acetyloxy)-1-{7-methyl-6-[(methylsulfonyl)oxy]-1,3-benzodioxol-4-yl}ethyl)-3-(benzyloxy)-4-methoxy-5-methyl-12-methylene-10-oxo-11,13-diazatricyclo[7.3.1.0~2,7~]trideca-2,4,6-triene-13-carboxylate C39H44N2O12S 详情 详情

合成路线14

The hydrolysis of the mesylate group of (XXVI) with NaOH in refluxing MeOH/water, followed by reaction with Ac2O and pyridine gives the diacetate (XXVII). The cleavage of the Boc group of (XXVII) by means of TFA in dichloromethane, followed by reprotection with Troc-Cl and NaHCO3 in dichloromethane yields the expected compound (XXVIII). The reaction of (XXVIII) with dimethyldioxirane and CSA in MeOH/acetone affords the acid-sensitive epoxide (XXIX), which, without isolation, is treated with MeOH and CSA to provide the methoxy alcohol (XXX). The reduction of (XXX) with NaBH3CN and TFA provides the chiral alcohol (XXXI) as a single isomer, which is protected with Tbdms-Cl and imidazole to give the silyl ether (XXXII). Cleavage of the Ac groups of (XXXII) by means of guanidinium nitrate and NaOMe in methanol/dichloromethane yields the dihydroxy compound (XXXIII).

参考文献 中间体
【1】 Abe, M.; Yanagisawa, A.; Tohma, S.; Kan, T.; Fukuyama, T.; Endo, A.; Total synthesis of ecteinascidin 743. J Am Chem Soc 2002, 124, 23, 6552.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXVI) 58624 tert-butyl (1R,9S)-11-((1R)-2-(acetyloxy)-1-{7-methyl-6-[(methylsulfonyl)oxy]-1,3-benzodioxol-4-yl}ethyl)-3-(benzyloxy)-4-methoxy-5-methyl-12-methylene-10-oxo-11,13-diazatricyclo[7.3.1.0~2,7~]trideca-2,4,6-triene-13-carboxylate C39H44N2O12S 详情 详情
(XXVII) 58625 tert-butyl (1R,9S)-11-{(1R)-2-(acetyloxy)-1-[6-(acetyloxy)-7-methyl-1,3-benzodioxol-4-yl]ethyl}-3-(benzyloxy)-4-methoxy-5-methyl-12-methylene-10-oxo-11,13-diazatricyclo[7.3.1.0~2,7~]trideca-2,4,6-triene-13-carboxylate C40H44N2O11 详情 详情
(XXVIII) 58626 2,2,2-trichloroethyl (1R,9S)-11-{(1R)-2-(acetyloxy)-1-[6-(acetyloxy)-7-methyl-1,3-benzodioxol-4-yl]ethyl}-3-(benzyloxy)-4-methoxy-5-methyl-12-methylene-10-oxo-11,13-diazatricyclo[7.3.1.0~2,7~]trideca-2,4,6-triene-13-carboxylate C38H37Cl3N2O11 详情 详情
(XXIX) 58627 　 C38H37Cl3N2O12 详情 详情
(XXX) 58628 2,2,2-trichloroethyl (1R,9S)-11-{(1R)-2-(acetyloxy)-1-[6-(acetyloxy)-7-methyl-1,3-benzodioxol-4-yl]ethyl}-3-(benzyloxy)-12-(hydroxymethyl)-4,12-dimethoxy-5-methyl-10-oxo-11,13-diazatricyclo[7.3.1.0~2,7~]trideca-2,4,6-triene-13-carboxylate C39H41Cl3N2O13 详情 详情
(XXXI) 58629 2,2,2-trichloroethyl (1R,9S,12R)-11-{(1R)-2-(acetyloxy)-1-[6-(acetyloxy)-7-methyl-1,3-benzodioxol-4-yl]ethyl}-3-(benzyloxy)-12-(hydroxymethyl)-4-methoxy-5-methyl-10-oxo-11,13-diazatricyclo[7.3.1.0~2,7~]trideca-2,4,6-triene-13-carboxylate C38H39Cl3N2O12 详情 详情
(XXXII) 58630 2,2,2-trichloroethyl (1R,9S,12R)-11-{(1R)-2-(acetyloxy)-1-[6-(acetyloxy)-7-methyl-1,3-benzodioxol-4-yl]ethyl}-3-(benzyloxy)-12-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-methoxy-5-methyl-10-oxo-11,13-diazatricyclo[7.3.1.0~2,7~]trideca-2,4,6-triene-1 C44H53Cl3N2O12Si 详情 详情
(XXXIII) 58631 2,2,2-trichloroethyl (1R,9S,12R)-3-(benzyloxy)-12-({[tert-butyl(dimethyl)silyl]oxy}methyl)-11-[(1R)-2-hydroxy-1-(6-hydroxy-7-methyl-1,3-benzodioxol-4-yl)ethyl]-4-methoxy-5-methyl-10-oxo-11,13-diazatricyclo[7.3.1.0~2,7~]trideca-2,4,6-triene-13-carbox C40H49Cl3N2O10Si 详情 详情

合成路线15

The selective protection of the phenolic OH of (XXXIII) by means of benzyl bromide and K2CO3 in refluxing acetonitrile gives the benzyl ether (XXXIV), which is reductocyclized by means of Red-Al in THF to yield the oxazolidine (XXXV). The cleavage of the oxazolidine ring of (XXXV) by means of Tms-CN and BF3/Et2O in dichloromethane affords the hydroxy nitrile (XXXVI), which is treated with Ac2O and pyridine to provide the acetate (XXXVII). The desilylation of (XXXVII) with HF in acetonitrile, followed by oxidation with DMP gives the carbaldehyde (XXXVIII), which is submitted to hydrogenolysis of the benzyl ethers by means of H2 over Pd/C in THF, performing a simultaneous cyclization to yield the pentacyclic compound (XXXIX). The reaction of (XXXIX) with allyl bromide (XL) and DIEA affords the allyl ether (XLI), which is treated with K2CO3 in methanol to provide the carbinol (XLII). The reaction of (XLII) with L-cysteine derivative (XLIII) by means of WSCD and DMAP in dichloromethane gives the corresponding ester (XLIV).

参考文献 中间体
【1】 Abe, M.; Yanagisawa, A.; Tohma, S.; Kan, T.; Fukuyama, T.; Endo, A.; Total synthesis of ecteinascidin 743. J Am Chem Soc 2002, 124, 23, 6552.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXIX) 58637 2,2,2-trichloroethyl (1R,2R,3S,13R,15R,16S)-13-[(acetyloxy)methyl]-15-cyano-3,5,22-trihydroxy-21-methoxy-6,20-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-hexaene-24-carboxylate C30H30Cl3N3O10 详情 详情
(XXXIII) 58631 2,2,2-trichloroethyl (1R,9S,12R)-3-(benzyloxy)-12-({[tert-butyl(dimethyl)silyl]oxy}methyl)-11-[(1R)-2-hydroxy-1-(6-hydroxy-7-methyl-1,3-benzodioxol-4-yl)ethyl]-4-methoxy-5-methyl-10-oxo-11,13-diazatricyclo[7.3.1.0~2,7~]trideca-2,4,6-triene-13-carbox C40H49Cl3N2O10Si 详情 详情
(XXXIV) 58632 2,2,2-trichloroethyl (1R,9S,12R)-3-(benzyloxy)-11-{(1R)-1-[6-(benzyloxy)-7-methyl-1,3-benzodioxol-4-yl]-2-hydroxyethyl}-12-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-methoxy-5-methyl-10-oxo-11,13-diazatricyclo[7.3.1.0~2,7~]trideca-2,4,6-triene-13-ca C47H55Cl3N2O10Si 详情 详情
(XXXV) 58633 2,2,2-trichloroethyl (1R,9S,10S,13R,15R)-3-(benzyloxy)-13-[6-(benzyloxy)-7-methyl-1,3-benzodioxol-4-yl]-15-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-methoxy-5-methyl-11-oxa-14,16-diazatetracyclo[7.6.1.0~2,7~.0~10,14~]hexadeca-2,4,6-triene-16-carbox C47H55Cl3N2O9Si 详情 详情
(XXXVI) 58634 2,2,2-trichloroethyl (1R,9S,10R,12R)-3-(benzyloxy)-11-{(1R)-1-[6-(benzyloxy)-7-methyl-1,3-benzodioxol-4-yl]-2-hydroxyethyl}-12-({[tert-butyl(dimethyl)silyl]oxy}methyl)-10-cyano-4-methoxy-5-methyl-11,13-diazatricyclo[7.3.1.0~2,7~]trideca-2,4,6-triene C48H56Cl3N3O9Si 详情 详情
(XXXVII) 58635 2,2,2-trichloroethyl (1R,9S,10R,12R)-11-{(1R)-2-(acetyloxy)-1-[6-(benzyloxy)-7-methyl-1,3-benzodioxol-4-yl]ethyl}-3-(benzyloxy)-12-({[tert-butyl(dimethyl)silyl]oxy}methyl)-10-cyano-4-methoxy-5-methyl-11,13-diazatricyclo[7.3.1.0~2,7~]trideca-2,4,6-tr C50H58Cl3N3O10Si 详情 详情
(XXXVIII) 58636 2,2,2-trichloroethyl (1R,9S,10R,12R)-11-{(1R)-2-(acetyloxy)-1-[6-(benzyloxy)-7-methyl-1,3-benzodioxol-4-yl]ethyl}-3-(benzyloxy)-10-cyano-12-formyl-4-methoxy-5-methyl-11,13-diazatricyclo[7.3.1.0~2,7~]trideca-2,4,6-triene-13-carboxylate C44H42Cl3N3O10 详情 详情
(XL) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XLI) 58638 2,2,2-trichloroethyl (1R,2R,3S,13R,15R,16S)-13-[(acetyloxy)methyl]-22-(allyloxy)-15-cyano-3,5-dihydroxy-21-methoxy-6,20-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-hexaene-24-carboxylate C33H34Cl3N3O10 详情 详情
(XLII) 58639 2,2,2-trichloroethyl (1R,2R,3S,13R,15R,16S)-22-(allyloxy)-15-cyano-3,5-dihydroxy-13-(hydroxymethyl)-21-methoxy-6,20-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-hexaene-24-carboxylate C31H32Cl3N3O9 详情 详情
(XLIII) 58640 (2R)-3-(acetylsulfanyl)-2-{[(allyloxy)carbonyl]amino}propanoic acid C9H13NO5S 详情 详情
(XLIV) 58641 2,2,2-trichloroethyl (1R,2R,3S,13R,15R,16S)-13-{[((2R)-3-(acetylsulfanyl)-2-{[(allyloxy)carbonyl]amino}propanoyl)oxy]methyl}-22-(allyloxy)-15-cyano-3,5-dihydroxy-21-methoxy-6,20-dimethyl-8,10-dioxa-14,24-diazahexacyclo[14.7.1.0~2,14~.0~4,12~.0~7,11~ C40H43Cl3N4O13S 详情 详情

合成路线16

Cleavage of the thioacetate bond of (XLIV) by means of hydrazine yields the thiol (XLV), which is cyclized by means of TFA in trifluoroethanol under high dilution conditions to afford the macrocyclic compound (XLVI). The reaction of (XLVI) with Ac2O and pyridine provides the acetate (XLVII), which is treated with Zn and HOAc in ethyl ether to eliminate the troc-protecting group, yielding (XLVIII). The reductive methylation of the NH group of (XLVIII) by means of HCHO, NaBH3CN and HOAc in methanol affords the N-methylamine derivative (XLIX), whose Alloc and ally ether groups are simultaneously eliminated by treatment with PdCl2(PPh3)2 and Bu3SnH in dichloromethane to provide the aminophenol (L). The transamination reaction of (L) with 4-formyl-1-methylpyridinium benzenesulfonate (FMPBS) and DBU in DMF/dichloromethane gives the alpha-ketolactone (LI).

参考文献 中间体
【1】 Abe, M.; Yanagisawa, A.; Tohma, S.; Kan, T.; Fukuyama, T.; Endo, A.; Total synthesis of ecteinascidin 743. J Am Chem Soc 2002, 124, 23, 6552.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XLIV) 58641 2,2,2-trichloroethyl (1R,2R,3S,13R,15R,16S)-13-{[((2R)-3-(acetylsulfanyl)-2-{[(allyloxy)carbonyl]amino}propanoyl)oxy]methyl}-22-(allyloxy)-15-cyano-3,5-dihydroxy-21-methoxy-6,20-dimethyl-8,10-dioxa-14,24-diazahexacyclo[14.7.1.0~2,14~.0~4,12~.0~7,11~ C40H43Cl3N4O13S 详情 详情
(XLV) 58642 2,2,2-trichloroethyl (1R,2R,3S,13R,15R,16S)-22-(allyloxy)-13-{[((2R)-2-{[(allyloxy)carbonyl]amino}-3-sulfanylpropanoyl)oxy]methyl}-15-cyano-3,5-dihydroxy-21-methoxy-6,20-dimethyl-8,10-dioxa-14,24-diazahexacyclo[14.7.1.0~2,14~.0~4,12~.0~7,11~.0~18,23 C38H41Cl3N4O12S 详情 详情
(XLVI) 58643 2,2,2-trichloroethyl (1R,2R,3R,11S,12R,14R,26R)-5-(allyloxy)-26-{[(allyloxy)carbonyl]amino}-12-cyano-22-hydroxy-6-methoxy-7,21-dimethyl-27-oxo-17,19,28-trioxa-24-thia-13,30-diazaheptacyclo[12.9.6.1~3,11~.0~2,13~.0~4,9~.0~15,23~.0~16,20~]triaconta-4,6,8,15,20,22-hexaen-22-yl acetate C38H39Cl3N4O11S 详情 详情
(XLVII) 58644 2,2,2-trichloroethyl (1R,2R,3R,11S,12R,14R,26R)-22-(acetyloxy)-5-(allyloxy)-26-{[(allyloxy)carbonyl]amino}-12-cyano-6-methoxy-7,21-dimethyl-27-oxo-17,19,28-trioxa-24-thia-13,30-diazaheptacyclo[12.9.6.1~3,11~.0~2,13~.0~4,9~.0~15,23~.0~16,20~]triaconta-4,6,8,15,20,22-hexaen-22-yl acetate C40H41Cl3N4O12S 详情 详情
(XLVIII) 58645 (1R,2R,3R,11S,12R,14R,26R)-5-(allyloxy)-26-{[(allyloxy)carbonyl]amino}-12-cyano-6-methoxy-7,21-dimethyl-27-oxo-17,19,28-trioxa-24-thia-13,30-diazaheptacyclo[12.9.6.1~3,11~.0~2,13~.0~4,9~.0~15,23~.0~16,20~]triaconta-4,6,8,15,20,22-hexaen-22-yl acetate C37H40N4O10S 详情 详情
(XLIX) 58646 (1R,2R,3R,11S,12R,14R,26R)-5-(allyloxy)-26-{[(allyloxy)carbonyl]amino}-12-cyano-6-methoxy-7,21,30-trimethyl-27-oxo-17,19,28-trioxa-24-thia-13,30-diazaheptacyclo[12.9.6.1~3,11~.0~2,13~.0~4,9~.0~15,23~.0~16,20~]triaconta-4,6,8,15,20,22-hexaen-22-yl acetate C38H42N4O10S 详情 详情
(L) 58647 (1R,2R,3R,11S,12R,14R,26R)-26-amino-12-cyano-5-hydroxy-6-methoxy-7,21,30-trimethyl-27-oxo-17,19,28-trioxa-24-thia-13,30-diazaheptacyclo[12.9.6.1~3,11~.0~2,13~.0~4,9~.0~15,23~.0~16,20~]triaconta-4,6,8,15,20,22-hexaen-22-yl acetate C31H34N4O8S 详情 详情
(LI) 58648 (1R,2R,3R,11S,12R,14R)-12-cyano-5-hydroxy-6-methoxy-7,21,30-trimethyl-26,27-dioxo-17,19,28-trioxa-24-thia-13,30-diazaheptacyclo[12.9.6.1~3,11~.0~2,13~.0~4,9~.0~15,23~.0~16,20~]triaconta-4,6,8,15,20,22-hexaen-22-yl acetate C31H31N3O9S 详情 详情

合成路线17

The Pictet-Spengler cyclization of (LI) with 2-(3-hydroxy-4-methoxyphenyl)ethylamine (LII) by means of NaOAc in ethanol yields the spiro-tetrahydroisoquinoline (LIII). Finally, the nitrile group of (LIII) is treated with AgNO3 in acetonitrile/water to afford the target Ecteinascidin 743.

参考文献 中间体
【1】 Abe, M.; Yanagisawa, A.; Tohma, S.; Kan, T.; Fukuyama, T.; Endo, A.; Total synthesis of ecteinascidin 743. J Am Chem Soc 2002, 124, 23, 6552.
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) 58648 (1R,2R,3R,11S,12R,14R)-12-cyano-5-hydroxy-6-methoxy-7,21,30-trimethyl-26,27-dioxo-17,19,28-trioxa-24-thia-13,30-diazaheptacyclo[12.9.6.1~3,11~.0~2,13~.0~4,9~.0~15,23~.0~16,20~]triaconta-4,6,8,15,20,22-hexaen-22-yl acetate C31H31N3O9S 详情 详情
(LII) 36471 5-(2-aminoethyl)-2-methoxyphenol C9H13NO2 详情 详情
(LIII) 58649 　 C40H42N4O10S 详情 详情
Extended Information
Drug NewChemical Entity Original Patent(1)