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【结 构 式】 
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【分子编号】46163 【品名】(4R,5S)-4-methyl-5-phenyl-3-propionyl-1,3-oxazolidin-2-one 【CA登记号】 |
【 分 子 式 】C13H15NO3 【 分 子 量 】233.26704 【元素组成】C 66.94% H 6.48% N 6% O 20.58% |
合成路线1
该中间体在本合成路线中的序号：(II)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 |
合成路线2
该中间体在本合成路线中的序号：(I)Synthesis of intermediate triphenylphosphonium salt (VII): The condensation of the chiral oxazolidinone (I) with cinnamyl bromide (II) by means of NaHMDS in THF gives the adduct (III), which is treated with LiBH4 in Et2O/water to yield the alcohol (IV). The protection of (IV) with Tbdms-Cl and imidazole in DMF affords the silyl ether (V), which is treated with ozone and reduced with NaBH4 to provide the alcohol (VI). The reaction of (VI) with I2 and PPh3 gives the desired triphenylphosphonium iodide (VII).
| 【1】 Mulzer, J.; et al.; A novel highly stereoselective total synthesis of epothilone B and of its (12R,13R) acetonide. Tetrahedron Lett 2000, 41, 40, 7635. |
| 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) | 46163 | (4R,5S)-4-methyl-5-phenyl-3-propionyl-1,3-oxazolidin-2-one | C13H15NO3 | 详情 | 详情 | |
| (II) | 21131 | 1-[(E)-3-bromo-1-propenyl]benzene | 4392-24-9 | C9H9Br | 详情 | 详情 |
| (III) | 46164 | (4R,5S)-4-methyl-3-[(2S,4E)-2-methyl-5-phenyl-4-pentenoyl]-5-phenyl-1,3-oxazolidin-2-one | C22H23NO3 | 详情 | 详情 | |
| (IV) | 46165 | (2S,4E)-2-methyl-5-phenyl-4-penten-1-ol | C12H16O | 详情 | 详情 | |
| (V) | 46166 | tert-butyl(dimethyl)silyl (2S,4E)-2-methyl-5-phenyl-4-pentenyl ether; tert-butyl(dimethyl)[[(2S,4E)-2-methyl-5-phenyl-4-pentenyl]oxy]silane | C18H30OSi | 详情 | 详情 | |
| (VI) | 46167 | (3S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-1-butanol | C11H26O2Si | 详情 | 详情 | |
| (VII) | 46168 | ((3S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methylbutyl)(triphenyl)phosphonium iodide | C29H40IOPSi | 详情 | 详情 |