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【结 构 式】 
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【分子编号】52709 【品名】(2S,3R)-3-{[(2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propanoyl]oxy}-2-[(tert-butoxycarbonyl)amino]butanoic acid 【CA登记号】 |
【 分 子 式 】C28H36N2O9 【 分 子 量 】544.60192 【元素组成】C 61.75% H 6.66% N 5.14% O 26.44% |
合成路线1
该中间体在本合成路线中的序号：(VI)The modified tyrosine building block (II) was prepared by alkylation of N-Cbz-L-tyrosine (I) at both the phenolic OH and the NH groups employing dimethyl sulfate under phase-transfer conditions. N-Boc-L-Threonine benzyl ether (III) was converted to the corresponding (triethylsilyl)ethoxymethyl ester, and the O-benzyl group was subsequently removed by catalytic hydrogenolysis to afford (IV). Coupling between the tyrosine (II) and threonine (IV) derivatives using DCC and DMAP gave rise to the protected didepsipeptide (V). The SEM protecting group was then cleaved by means of HF in acetonitrile, yielding intermediate (VI)
| 【1】 Jou, G.; Gonzalez, I.; Albericio, F.; Lloyd-Williams, P.; Giralt, E.; Total synthesis of dehydrodidemnin B. Use of uronium and phosphonium salt coupling reagents in peptide synthesis in solution. J Org Chem 1997, 62, 2, 354. |
| 【2】 Giralt Lledo, E.; Albericio Palomera, F.; Lloyd-Williams, P.; Gonzalez Valcarcel, I.; Jou Prat, G.; Gomez Gonzalez, A.; Manzanares Secades, I. (PharmaMar, SA); Process for the preparation of didemnine A. ES 2102322 . |
| 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) | 39328 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-(4-hydroxyphenyl)propionic acid | C17H17NO5 | 详情 | 详情 | |
| (II) | 50747 | (2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propionic acid | C19H21NO5 | 详情 | 详情 | |
| (III) | 50782 | (2S,3R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]butyric acid | C16H23NO5 | 详情 | 详情 | |
| (IV) | 50746 | [2-(trimethylsilyl)ethoxy]methyl (2S,3R)-2-[(tert-butoxycarbonyl)amino]-3-hydroxybutanoate | C15H31NO6Si | 详情 | 详情 | |
| (V) | 62532 | [2-(trimethylsilyl)ethoxy]methyl (2S,3R)-3-{[(2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propanoyl]oxy}-2-[(tert-butoxycarbonyl)amino]butanoate | C34H50N2O10Si | 详情 | 详情 | |
| (VI) | 52709 | (2S,3R)-3-{[(2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propanoyl]oxy}-2-[(tert-butoxycarbonyl)amino]butanoic acid | C28H36N2O9 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)Coupling between segments (VI) and (XXI) by means of HBTU gave rise to the depsipeptide (XXII). Simultaneous deprotection of the C- and N-terminal functions of (XXII) by hydrogenolysis led to the linear precursor (XXIII), which was then cyclized to (XXIV) in the presence of HATU and HOAt
| 【1】 Jou, G.; Gonzalez, I.; Albericio, F.; Lloyd-Williams, P.; Giralt, E.; Total synthesis of dehydrodidemnin B. Use of uronium and phosphonium salt coupling reagents in peptide synthesis in solution. J Org Chem 1997, 62, 2, 354. |
| 【2】 Giralt Lledo, E.; Albericio Palomera, F.; Lloyd-Williams, P.; Gonzalez Valcarcel, I.; Jou Prat, G.; Gomez Gonzalez, A.; Manzanares Secades, I. (PharmaMar, SA); Process for the preparation of didemnine A. ES 2102322 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 52709 | (2S,3R)-3-{[(2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propanoyl]oxy}-2-[(tert-butoxycarbonyl)amino]butanoic acid | C28H36N2O9 | 详情 | 详情 | |
| (XXI) | 62536 | benzyl (2S)-1-{(2S)-2-[((4S)-4-{[(3S,4R,5S)-4-amino-3-hydroxy-5-methylheptanoyl]oxy}-2,5-dimethyl-3-oxohexanoyl)amino]-4-methylpentanoyl}-2-pyrrolidinecarboxylate | C34H53N3O8 | 详情 | 详情 | |
| (XXII) | 62537 | benzyl (2S)-1-{(2S,7S,11S,12R,15S,16R,19S)-15-[(tert-butoxycarbonyl)amino]-11-hydroxy-2-isobutyl-7-isopropyl-19-(4-methoxybenzyl)-5,16,20-trimethyl-12-[(1S)-1-methylpropyl]-4,6,9,14,18,21-hexaoxo-23-phenyl-8,17,22-trioxa-3,13,20-triazatricos-1-anoyl | C62H87N5O16 | 详情 | 详情 | |
| (XXIII) | 62538 | (2S)-1-{(2S,7S,11S,12R,15S,16R,19S)-15-[(tert-butoxycarbonyl)amino]-11-hydroxy-2-isobutyl-7-isopropyl-19-(4-methoxybenzyl)-5,16-dimethyl-12-[(1S)-1-methylpropyl]-4,6,9,14,18-pentaoxo-8,17-dioxa-3,13,20-triazahenicos-1-anoyl}-2-pyrrolidinecarboxylic | C47H75N5O14 | 详情 | 详情 | |
| (XXIV) | 62539 | tert-butyl (3S,6R,7S,10R,11S,15S,17S,20S,25aS)-11-hydroxy-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]-1,4,8,13,16,18,21-heptaoxodocosahydro-15H-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotricosin-7-ylc | C47H73N5O13 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)N-Boc-L-Threonine (LVI) was protected as the corresponding phenacyl ester (LVII) by treatment with 2-bromoacetophenone and Et3N. Esterification of (LVII) with the modified tyrosine building block (II) yielded the protected didepsipeptide (LVIII). Removal of the phenacyl ester group of (LVIII) under reductive conditions provided the carboxylic acid (VI). Coupling of acid (VI) with the depsipeptide segment (XXI), followed by deprotection by hydrogenolysis furnished the linear precursor (XXIII). Macrocyclization of (XXIII) using HATU and subsequent acidic Boc group cleavage led to the macrocyclic amine (XXV)
| 【1】 Edge, A. (Diacrin, Inc.); Method for improving graft acceptance in a recipient by administration of a cytokine profile altering agent. WO 0051630 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10315 | 2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone | 70-11-1 | C8H7BrO | 详情 | 详情 | |
| (II) | 50747 | (2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propionic acid | C19H21NO5 | 详情 | 详情 | |
| (VI) | 52709 | (2S,3R)-3-{[(2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propanoyl]oxy}-2-[(tert-butoxycarbonyl)amino]butanoic acid | C28H36N2O9 | 详情 | 详情 | |
| (XXI) | 62536 | benzyl (2S)-1-{(2S)-2-[((4S)-4-{[(3S,4R,5S)-4-amino-3-hydroxy-5-methylheptanoyl]oxy}-2,5-dimethyl-3-oxohexanoyl)amino]-4-methylpentanoyl}-2-pyrrolidinecarboxylate | C34H53N3O8 | 详情 | 详情 | |
| (XXIII) | 62538 | (2S)-1-{(2S,7S,11S,12R,15S,16R,19S)-15-[(tert-butoxycarbonyl)amino]-11-hydroxy-2-isobutyl-7-isopropyl-19-(4-methoxybenzyl)-5,16-dimethyl-12-[(1S)-1-methylpropyl]-4,6,9,14,18-pentaoxo-8,17-dioxa-3,13,20-triazahenicos-1-anoyl}-2-pyrrolidinecarboxylic | C47H75N5O14 | 详情 | 详情 | |
| (XXV) | 50768 | (3S,6R,7S,10R,11S,15S,17S,20S,25aS)-7-amino-11-hydroxy-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]tetradecahydro-15H-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotricosine-1,4,8,13,16,18,21(17H)-heptone | C42H65N5O11 | 详情 | 详情 | |
| (LVI) | 50745 | N-BOC-L-threonine; Boc-Threonine; N-tert-Butoxycarbonyl-L-threonine; N-(tert-Butoxycarbonyl)-L-threonine; BOC-L-Threonine | 2592-18-9 | C9H17NO5 | 详情 | 详情 |
| (LVII) | 62565 | 2-oxo-2-phenylethyl (2S,3R)-2-[(tert-butoxycarbonyl)amino]-3-hydroxybutanoate | C17H23NO6 | 详情 | 详情 | |
| (LVIII) | 62566 | 2-oxo-2-phenylethyl (2S,3R)-3-{[(2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propanoyl]oxy}-2-[(tert-butoxycarbonyl)amino]butanoate | C36H42N2O10 | 详情 | 详情 |