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【结 构 式】 
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【分子编号】49332 【品名】(2R)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutyric acid 【CA登记号】 |
【 分 子 式 】C13H17NO4 【 分 子 量 】251.28232 【元素组成】C 62.14% H 6.82% N 5.57% O 25.47% |
合成路线1
该中间体在本合成路线中的序号：(XXVIII)The condensation of intermediate (XXI) with intermediate (XV) by means of BOP and DIEA gives the dipeptide (XXIV) partially racemized, which is easily purified by chromatography. The deprotection of (XXIV) by means of TFA yields dipeptide (XXV), which is condensed with intermediate (VIII) by means of BOP and DIEA to afford tripeptide (XXVI). The deprotection of (XXVI) by means of TFA yields tripeptide (XXVII), which is condensed with N-(benzyloxycarbonyl)-L-valine (XXVIII) by means of BrOP and DIEA to afford tetrapeptide (XXIX). The deprotection of (XXIX) by means of HBr provides tetrapeptide (XXX), which is finally condensed with N,N-dimethyl-L-valine (XXXI) by means of COMMOD to afford the target dolastatine.
| 【1】 Roux, F.; et al.; Synthesis of dolastatin-10 and [R-Doe]-dolastatin-10. Tetrahedron 1994, 50, 18, 5345. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 54599 | (3R,4S)-4-[(tert-butoxycarbonyl)(methyl)amino]-3-methoxy-5-methylheptanoic acid | C15H29NO5 | 详情 | 详情 | |
| (XV) | 23520 | (2R,3R)-3-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-3-methoxy-2-methylpropionic acid | C14H25NO5 | 详情 | 详情 | |
| (XXI) | 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 | |
| (XXIV) | 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 | |
| (XXV) | 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 | |
| (XXVI) | 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 | |
| (XXVII) | 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 | |
| (XXVIII) | 49332 | (2R)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutyric acid | C13H17NO4 | 详情 | 详情 | |
| (XXIX) | 54612 | benzyl (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 | C43H61N5O7S | 详情 | 详情 | |
| (XXX) | 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 | |
| (XXXI) | 23518 | (2S)-2-(dimethylamino)-3-methylbutyric acid | C7H15NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIII)Chiral tripeptide intermediate (XV): The deprotection of perhydropyridazine carboxylic acid methyl ester (VII) with TFA in dichloromethane gives ester (VIII), which is condensed with N-(benzyloxycarbonyl)-3-hydroxy-L-tyrosine (IX) by means of HBTU and TEA in acetonitrile to yield the dipeptide (X). The protection of the phenolic OH group of (X) with Boc2O and TEA In dichloromethane affords (XI), which is selectively deprotected with H2 over Pd/C in ethanol to provide dipeptide (XII). The condensation of (XII) with N-(benzyloxycarbonyl)-L-valine (XIII) by means of HBTU as before gives the protected tripeptide (XIV), which is finally treated with H2 over Pd/C in ethanol to provide the target tripeptide intermediate (XV)
| 【1】 Duan, M.S.; Paquette, L.A.; Enantioselective total synthesis of the cyclophilin-binding immunosuppressive agent sanglifehrin A. Angew Chem. Int Ed 2001, 40, 19, 3632. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 60105 | 1,2-di(tert-butyl) 3-methyl (3S)tetrahydro-1,2,3-pyridazinetricarboxylate | C16H28N2O6 | 详情 | 详情 | |
| (VIII) | 60106 | methyl (3S)hexahydro-3-pyridazinecarboxylate | C6H12N2O2 | 详情 | 详情 | |
| (IX) | 60107 | (2S)-2-{[(benzyloxy)carbonyl]amino}-3-(3-hydroxyphenyl)propanoic acid | C17H17NO5 | 详情 | 详情 | |
| (X) | 60108 | methyl (3S)-1-[(2S)-2-{[(benzyloxy)carbonyl]amino}-3-(3-hydroxyphenyl)propanoyl]hexahydro-3-pyridazinecarboxylate | C23H27N3O6 | 详情 | 详情 | |
| (XI) | 60109 | methyl (3S)-1-((2S)-2-{[(benzyloxy)carbonyl]amino}-3-{3-[(tert-butoxycarbonyl)oxy]phenyl}propanoyl)hexahydro-3-pyridazinecarboxylate | C28H35N3O8 | 详情 | 详情 | |
| (XII) | 60110 | methyl (3S)-1-((2S)-2-amino-3-{3-[(tert-butoxycarbonyl)oxy]phenyl}propanoyl)hexahydro-3-pyridazinecarboxylate | C20H29N3O6 | 详情 | 详情 | |
| (XIII) | 49332 | (2R)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutyric acid | C13H17NO4 | 详情 | 详情 | |
| (XIV) | 60111 | methyl (3S)-1-((2S)-2-[((2S)-2-{[(benzyloxy)carbonyl]amino}-3-methylbutanoyl)amino]-3-{3-[(tert-butoxycarbonyl)oxy]phenyl}propanoyl)hexahydro-3-pyridazinecarboxylate | C33H44N4O9 | 详情 | 详情 | |
| (XV) | 60112 | methyl (3S)-1-((2S)-2-{[(2S)-2-amino-3-methylbutanoyl]amino}-3-{3-[(tert-butoxycarbonyl)oxy]phenyl}propanoyl)hexahydro-3-pyridazinecarboxylate | C25H38N4O7 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The synthesis of the carboxylic acid intermediate (VIII) has been performed as follows: The reaction of D-valine (I) with benzyl chloroformate and NaHCO3 gives the protected valine (II), which is esterified with pentafluorophenol and EDAC to yield the activated ester (III). The condensation of (III) with the lithium enolate of methyl acetate (IV) affords the beta ketoester (V), which is stereoselectively reduced with KBH4 and crystallized to afford the desired enantiomeric beta hydroxyester (VI). The silylation of (VI) with Tips-OTf and lutidine provides the silyl ether (VII), which is hydrolyzed with NaOH to give the desired carboxylic acid intermediate (VIII). The synthesis of the activated ester intermediate (XV) has been performed as follows: The reaction of L-valine (IX) with NaNO2 and H2SO4 gives the hydroxyacid (X), which is esterified with allyl bromide (XI) and K2CO3 to yield the allyl ester (XII). The condensation of (XII) with the intermediate (VIII) by means of EDAC and DMAP affords the adduct (XIII), which is treated with Pd(PPh3)4 to provide the carboxylic acid (XIV). Finally, this compound is esterified with C6F5-OTf to give the activated ester intermediate (XV).
| 【1】 Liang, B.; et al.; Total syntheses and biological investigations of tamandarins A and B and tamandarin A analogs. J Am Chem Soc 2001, 123, 19, 4469. |
| 【2】 Joullie, M.M.; et al.; Total synthesis of (-)-tamandarin B. Tetrahedron Lett 2000, 41, 49, 9373. |
| 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) | 21056 | (R)-(-)-Valine; D-Valine; (R)-alpha-Aminoisovaleric acid | 640-68-6 | C5H11NO2 | 详情 | 详情 |
| (II) | 49332 | (2R)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutyric acid | C13H17NO4 | 详情 | 详情 | |
| (III) | 49323 | 2,3,4,5,6-pentafluorophenyl (2R)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoate | C19H16F5NO4 | 详情 | 详情 | |
| (IV) | 49324 | C3H5LiO2 | 详情 | 详情 | ||
| (V) | 49325 | methyl (4R)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-oxohexanoate | C16H21NO5 | 详情 | 详情 | |
| (VI) | 49326 | methyl (3S,4R)-4-[[(benzyloxy)carbonyl]amino]-3-hydroxy-5-methylhexanoate | C16H23NO5 | 详情 | 详情 | |
| (VII) | 49327 | methyl (3S,4R)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]hexanoate | C25H43NO5Si | 详情 | 详情 | |
| (VIII) | 49328 | (3S,4R)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]hexanoic acid | C24H41NO5Si | 详情 | 详情 | |
| (IX) | 37828 | L-2-Amino-3-methylbutyric acid; L-2-Aminoisovaleric acid; 2-Aminoisovaleric acid; L-2-Amino-3-methylbutyric acid; L-alpha-Aminoisovaleric acid; L-valine; (S)-(+)-Valine; (S)-alpha-Aminoisovaleric acid | 72-18-4 | C5H11NO2 | 详情 | 详情 |
| (X) | 37829 | (2S)-2-hydroxy-3-methylbutyric acid | C5H10O3 | 详情 | 详情 | |
| (XI) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (XII) | 37830 | allyl (2S)-2-hydroxy-3-methylbutanoate | C8H14O3 | 详情 | 详情 | |
| (XIII) | 49329 | (1S)-1-[(allyloxy)carbonyl]-2-methylpropyl (3S,4R)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]hexanoate | C32H53NO7Si | 详情 | 详情 | |
| (XIV) | 49330 | (2S)-2-([(3S,4R)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]hexanoyl]oxy)-3-methylbutyric acid | C29H49NO7Si | 详情 | 详情 | |
| (XV) | 49331 | (1S)-2-methyl-1-[(2,3,4,5,6-pentafluorophenoxy)carbonyl]propyl (3S,4R)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]hexanoate | C35H48F5NO7Si | 详情 | 详情 |