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【结 构 式】 
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【分子编号】54615 【品名】(2R,3R)-3-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-3-hydroxy-2-methylpropanoic acid 【CA登记号】 |
【 分 子 式 】C13H23NO5 【 分 子 量 】273.32936 【元素组成】C 57.13% H 8.48% N 5.12% O 29.27% |
合成路线1
该中间体在本合成路线中的序号：(IV)The enantioselective condensation of N-Boc-L-prolinal (I) with the chiral 3-propionyloxazolidinone (II) by means of Bu2B-OTf in dichloromethane gives the chiral beta-hydroxyamide (III), which is submitted to elimination of the chiral auxiliary by hydrolysis with LiOH and H2O2 in THF/water to yield the hydroxyacid (IV). The methylation of (IV) with Me-I and NaH in THF affords the methoxyacid (V). The condensation of intermediate (V) with 2-phenyl-1(S)-(2-thiazolyl)ethylamine (VI) by means of (EtO)2P(O)CN and DIEA gives the dipeptide (VII). The deprotection of (VII) by means of TFA yields dipeptide (VIII), which is condensed with the beta-methoxy-gamma-aminoacid (IX) as before to afford tripeptide (X). The deprotection of (X) by means of TFA yields tripeptide (XI), which is condensed with N-Boc-L-valine (XII) by means of BopCl and DIEA to afford tetrapeptide (XIII). The deprotection of (XIII) by means of TFA provides tetrapeptide (XIV), which is finally condensed with N,N-dimethyl-L-valine (XV) by means of (EtO)2P(O)CN and TEA to afford the target dolastatine.
| 【1】 Hayashi, K.; et al.; An efficient total synthesis of dolastatin 10, an antineoplastic pentapeptide of marine origin. Pept Chem 1990, Pub. 1991, 43. |
| 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) | 16724 | tert-Butyl (2S)-2-formyltetrahydro-1H-pyrrole-1-carboxylate; tert-Butoxycarbonyl-L-prolinal | 69610-41-9 | C10H17NO3 | 详情 | 详情 |
| (II) | 46163 | (4R,5S)-4-methyl-5-phenyl-3-propionyl-1,3-oxazolidin-2-one | C13H15NO3 | 详情 | 详情 | |
| (III) | 54614 | tert-butyl (2S)-2-{(1R,2R)-1-hydroxy-2-methyl-3-[(4R,5S)-4-methyl-2-oxo-5-phenyl-1,3-oxazolidin-3-yl]-3-oxopropyl}-1-pyrrolidinecarboxylate | C23H32N2O6 | 详情 | 详情 | |
| (IV) | 54615 | (2R,3R)-3-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-3-hydroxy-2-methylpropanoic acid | C13H23NO5 | 详情 | 详情 | |
| (V) | 23520 | (2R,3R)-3-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-3-methoxy-2-methylpropionic acid | C14H25NO5 | 详情 | 详情 | |
| (VI) | 54607 | (1S)-2-phenyl-1-(1,3-thiazol-2-yl)-1-ethanamine; (1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethylamine | C11H12N2S | 详情 | 详情 | |
| (VII) | 54608 | tert-butyl (2S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl)-1-pyrrolidinecarboxylate | C25H35N3O4S | 详情 | 详情 | |
| (VIII) | 54609 | (2R,3R)-3-methoxy-2-methyl-N-[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]-3-[(2S)pyrrolidinyl]propanamide | C20H27N3O2S | 详情 | 详情 | |
| (IX) | 54599 | (3R,4S)-4-[(tert-butoxycarbonyl)(methyl)amino]-3-methoxy-5-methylheptanoic acid | C15H29NO5 | 详情 | 详情 | |
| (X) | 54610 | tert-butyl (1S,2R)-2-methoxy-4-[(2S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl)pyrrolidinyl]-1-[(1S)-1-methylpropyl]-4-oxobutyl(methyl)carbamate | C35H54N4O6S | 详情 | 详情 | |
| (XI) | 54611 | (2R,3R)-3-methoxy-3-{(2S)-1-[(3R,4S,5S)-3-methoxy-5-methyl-4-(methylamino)heptanoyl]pyrrolidinyl}-2-methyl-N-[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]propanamide | C30H46N4O4S | 详情 | 详情 | |
| (XII) | 19733 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid | C10H19NO4 | 详情 | 详情 | |
| (XIII) | 54616 | tert-butyl (1S)-1-{[{(1S,2R)-2-methoxy-4-[(2S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl)pyrrolidinyl]-1-[(1S)-1-methylpropyl]-4-oxobutyl}(methyl)amino]carbonyl}-2-methylpropylcarbamate | C40H63N5O7S | 详情 | 详情 | |
| (XIV) | 23518 | (2S)-2-(dimethylamino)-3-methylbutyric acid | C7H15NO2 | 详情 | 详情 | |
| (XV) | 54613 | (2S)-2-amino-N-{(1S,2R)-2-methoxy-4-[(2S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl)pyrrolidinyl]-1-[(1S)-1-methylpropyl]-4-oxobutyl}-N,3-dimethylbutanamide | C35H55N5O5S | 详情 | 详情 |