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【结 构 式】 
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【分子编号】58641 【品名】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~ 【CA登记号】 |
【 分 子 式 】C40H43Cl3N4O13S 【 分 子 量 】926.22468 【元素组成】C 51.87% H 4.68% Cl 11.48% N 6.05% O 22.46% S 3.46% |
合成路线1
该中间体在本合成路线中的序号：(XLIV)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).
| 【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2
该中间体在本合成路线中的序号：(XLIV)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).
| 【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 |