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【结 构 式】 
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【分子编号】16010 【品名】D-leucine 【CA登记号】328-38-1 |
【 分 子 式 】C6H13NO2 【 分 子 量 】131.17476 【元素组成】C 54.94% H 9.99% N 10.68% O 24.39% |
合成路线1
该中间体在本合成路线中的序号：(I)The treatment of D-leucine (I) with NaNO2, H2SO4 and NaBr gives 2(R)-bromo-5-methylpentanoic acid (II), which is esterified with isobutene and H2SO4 to the corresponding tert-butyl ester (III). The condensation of (III) with dibenzyl malonate (IV) by means of potassium tert-butoxide in DMF yields the malonyl derivative (V), which is treated with trifluoroacetic acid to hydrolyze the tert-butyl ester, and without isolation is condensed with L-phenylalanine methyl amide (VI) by means of hydroxybenzotriazole (HOBT) and dicyclohexylcarbodiimide (DCC), affording 4-benzyloxy-3-(benzyloxycarbonyl)-2(R)-isobutylsuccinyl-L-phenylalanine methylamide (VII). The elimination of the benzyl groups of (VII) by hydrogenolysis over Pd/C in ethanol gives the dicarboxylic acid (VIII), which by partial decarboxylation and reaction with aqueous formaldehyde and piperidine yields 4-hydroxy-2(R)-isobutyl-3-methylenesuccinyl-L-phenylalanine methylamide (IX). The addition of thiophene-2-thiol (X) to the double bond of (IX) affords 4-hydroxy-2(R)-isobutyl-3(S)-(2-thienylsulfanylmethyl)succinyl-L-phenylalanine methylamide (XI), which is finally treated with hydroxylamine and hydroxybenzotriazole in dichloromethane/DMF.
| 【1】 Ngo, J.; Graul, A.; Castaner, J.; Batimastat. Drugs Fut 1996, 21, 12, 1215. |
| 【2】 Campion, C.; Davidson, A.H.; Dickens, J.P.; Crimmin, M.J. (British Biotech plc); Hydroxamic acid based collagenase inhibitors. US 5240958; US 5310763; WO 9005719 . |
| 【3】 Beckett, R.P.; Crimmin, M.J.; Galloway, W.A.; Matrix metalloproteinase inhibitors in the treatment of rheumatoid arthritis and cancer. 205th ACS Natl Meet (March 28-April 2, Denver) 1993, Abst MEDI 147. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15926 | 2-methyl-1-propene; isobutylene | 115-11-7 | C4H8 | 详情 | 详情 | |
| (I) | 16010 | D-leucine | 328-38-1 | C6H13NO2 | 详情 | 详情 |
| (II) | 16011 | (2R)-2-bromo-4-methylpentanoic acid | C6H11BrO2 | 详情 | 详情 | |
| (III) | 16012 | tert-butyl (2R)-2-bromo-4-methylpentanoate | C10H19BrO2 | 详情 | 详情 | |
| (IV) | 16013 | dibenzyl malonate | 15014-25-2 | C17H16O4 | 详情 | 详情 |
| (V) | 16014 | 1,1-dibenzyl 2-(tert-butyl) (2R)-4-methyl-1,1,2-pentanetricarboxylate | C27H34O6 | 详情 | 详情 | |
| (VI) | 16015 | (2S)-2-amino-N-methyl-3-phenylpropanamide | C10H14N2O | 详情 | 详情 | |
| (VII) | 16016 | dibenzyl 2-[(1R)-1-([[(1S)-1-benzyl-2-(methylamino)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]malonate | C33H38N2O6 | 详情 | 详情 | |
| (VIII) | 16017 | 2-[(1R)-1-([[(1S)-1-benzyl-2-(methylamino)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]malonic acid | C19H26N2O6 | 详情 | 详情 | |
| (IX) | 16018 | 2-[(1R)-1-([[(1S)-1-benzyl-2-(methylamino)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]acrylic acid | C19H26N2O4 | 详情 | 详情 | |
| (X) | 16019 | 2-Thienylhydrosulfide; 2-Thiophenethiol | 7774-74-5 | C4H4S2 | 详情 | 详情 |
| (XI) | 16020 | (2S,3R)-3-([[(1S)-1-benzyl-2-(methylamino)-2-oxoethyl]amino]carbonyl)-5-methyl-2-[(2-thienylsulfanyl)methyl]hexanoic acid | C23H30N2O4S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXVI)Removal of the N-Boc protecting group of (XXIV) by means of HCl in dioxane generated the macrocyclic amine (XXV). The protected aminoacid (XXVII) was prepared by treatment of D-leucine (XXVI) with Boc2O, followed by N-methylation under phase-transfer conditions. Coupling of N-Boc-N-methyl-D-leucine (XXVII) with amine (XXV) provided amide (XXVIII). Then, acidic Boc group cleavage in (XXVIII) furnished didemnin A (XXIX)
| 【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 |
|---|---|---|---|---|---|---|
| (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 | |
| (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 | |
| (XXVI) | 16010 | D-leucine | 328-38-1 | C6H13NO2 | 详情 | 详情 |
| (XXVII) | 50788 | (2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-4-methylpentanoic acid | C12H23NO4 | 详情 | 详情 | |
| (XXVIII) | 62540 | tert-butyl (1R)-1-[({(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]dioxatetraazacyclotric | C54H86N6O14 | 详情 | 详情 | |
| (XXIX) | 50796 | (2R)-N-[(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-yl]-4-methyl-2-(methylamino)pentanamide | C49H78N6O12 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The esterification of D-leucine (I) with benzyl alcohol and HCl gives the corresponding ester (II), which is N-benzylated by reductocondensation with benzaldehyde and sodium cyanoborohydride yielding N-benzyl-D-leucine benzyl ester (III). The condensation of (III) with methyl phenyl phosphinyl chloride (IV) by means of N-methylmorpholine in dichloromethane affords the phosphinylamino derivative (V), which is treated with H2 over Pd/C in methanol to give N-benzyl-N-[methyl(phenyl)phosphinyl]-D-leucine (VI). The condensation of (VI) with O-benzylhydroxylamine (VII) by means of 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide (DEC) and HOBT in DMF yields the N-benzyl hydroxamic acid (VIII) as a diastereomeric mixture that is separated by flash chromatography providing the diastereomer (IX). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C in methanol.
| 【1】 Elst, L.V.; et al.; A multinuclear MR study of Gd-EOB-DTPA: Comprehensive preclinical characterization of an organ specific MRI contrast agent. Magn Reson Med 1997, 38, 4, 604. |
| 【2】 Taiwo, Y.O.; Pikul, S.; De, B.; McDow-Dunham, K.L. (The Procter & Gamble Co.); Phosphinic acid amides as matrix metalloprotease inhibitors. US 5830915; WO 9808853 . |
| 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) | 16010 | D-leucine | 328-38-1 | C6H13NO2 | 详情 | 详情 |
| (II) | 28648 | benzyl (2R)-2-amino-4-methylpentanoate | C13H19NO2 | 详情 | 详情 | |
| (III) | 28643 | benzyl (2R)-2-(benzylamino)-4-methylpentanoate | C20H25NO2 | 详情 | 详情 | |
| (IV) | 28644 | methyl(phenyl)phosphinic chloride | 5761-97-7 | C7H8ClOP | 详情 | 详情 |
| (V) | 28645 | benzyl (2R)-2-[benzyl[methyl(phenyl)phosphoryl]amino]-4-methylpentanoate | C27H32NO3P | 详情 | 详情 | |
| (VI) | 28646 | (2R)-2-[benzyl[methyl(phenyl)phosphoryl]amino]-4-methylpentanoic acid | C20H26NO3P | 详情 | 详情 | |
| (VII) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (VIII) | 28647 | (2R)-2-[benzyl[methyl(phenyl)phosphoryl]amino]-N-(benzyloxy)-4-methylpentanamide | C27H33N2O3P | 详情 | 详情 | |
| (IX) | 28649 | (2R)-2-[benzyl[methyl(phenyl)phosphoryl]amino]-N-(benzyloxy)-4-methylpentanamide | C27H33N2O3P | 详情 | 详情 |