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【结 构 式】 
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【分子编号】58624 【品名】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 【CA登记号】 |
【 分 子 式 】C39H44N2O12S 【 分 子 量 】764.85064 【元素组成】C 61.24% H 5.8% N 3.66% O 25.1% S 4.19% |
合成路线1
该中间体在本合成路线中的序号：(XXVI)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).
| 【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2
该中间体在本合成路线中的序号：(XXVI)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).
| 【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 |