|
【结 构 式】 
|
【分子编号】54599 【品名】(3R,4S)-4-[(tert-butoxycarbonyl)(methyl)amino]-3-methoxy-5-methylheptanoic acid 【CA登记号】 |
【 分 子 式 】C15H29NO5 【 分 子 量 】303.399 【元素组成】C 59.38% H 9.63% N 4.62% O 26.37% |
合成路线1
该中间体在本合成路线中的序号：(VIII)The reaction of N-Boc-L-isoleucine (I) with O-methylhydroxylamine (II) by means of PyBOP gives the corresponding amide (III), which is condensed with allylmagnesium bromide (IV) to afford the octenone (V). The reduction of (V) with NaBH4 yields the carbinol (VI), which is N- and O-methylated with Me-I and NaH to provide the dimethylated compound (VII). Finally, the terminal double bond of (VII) is oxidated by means of NaIO4 and RuO2 to furnish the desired intermediate, the amino acid (VIII).
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 30009 | (2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentanoic acid | 13139-16-7 | C11H21NO4 | 详情 | 详情 |
| (II) | 13361 | (Methoxyamino)methane; N,O-Dimethylhydroxylamine | 1117-97-1 | C2H7NO | 详情 | 详情 |
| (III) | 38788 | tert-butyl (1S,2S)-1-[[methoxy(methyl)amino]carbonyl]-2-methylbutylcarbamate | 3350-19-4 | C13H26N2O4 | 详情 | 详情 |
| (IV) | 10386 | Allyl(bromo)magnesium | 1730-25-2 | C3H5BrMg | 详情 | 详情 |
| (V) | 54596 | tert-butyl (1S)-1-(sec-butyl)-2-oxo-4-pentenylcarbamate | C14H25NO3 | 详情 | 详情 | |
| (VI) | 54597 | tert-butyl (1S,2R)-1-(sec-butyl)-2-hydroxy-4-pentenylcarbamate | C14H27NO3 | 详情 | 详情 | |
| (VII) | 54598 | tert-butyl (1S,2R)-1-(sec-butyl)-2-methoxy-4-pentenyl(methyl)carbamate | C16H31NO3 | 详情 | 详情 | |
| (VIII) | 54599 | (3R,4S)-4-[(tert-butoxycarbonyl)(methyl)amino]-3-methoxy-5-methylheptanoic acid | C15H29NO5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)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3
该中间体在本合成路线中的序号：(IX)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4
该中间体在本合成路线中的序号：(VI)The reaction of N-Boc-L-isoleucine (I) with the lithium derivative of tert-butyl acetate (II) by means of CDI in THF gives the beta-ketoester (III), which is reduced with NaBH4 in methanol to yield the desired (R)-alcohol (IV). N- and O-methylation of (IV) by means of LiHMDS and Me-OTf in HMPA/THF affords the fully methylated ester (V), which is finally hydrolyzed with HCO2H to furnish the desired intermediate, the methylated amino acid (VI).
| 【1】 Tomioka, K.; et al.; An expeditious synthesis of dolastatin 10. Tetrahedron 1991, 32, 21, 2395. |
| 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) | 30009 | (2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentanoic acid | 13139-16-7 | C11H21NO4 | 详情 | 详情 |
| (II) | 15593 | [2-(tert-butoxy)-2-oxoethyl]lithium | C6H11LiO2 | 详情 | 详情 | |
| (III) | 54617 | tert-butyl (4S,5S)-4-[(tert-butoxycarbonyl)amino]-5-methyl-3-oxoheptanoate | C17H31NO5 | 详情 | 详情 | |
| (IV) | 54618 | tert-butyl (3R,4S,5S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-5-methylheptanoate | C17H33NO5 | 详情 | 详情 | |
| (V) | 54619 | tert-butyl (3R,4S,5S)-4-[(tert-butoxycarbonyl)(methyl)amino]-3-methoxy-5-methylheptanoate | C19H37NO5 | 详情 | 详情 | |
| (VI) | 54599 | (3R,4S)-4-[(tert-butoxycarbonyl)(methyl)amino]-3-methoxy-5-methylheptanoic acid | C15H29NO5 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)The condensation of intermediate (XIX) with intermediate (XII) by means of DEC and TEA gives the dipeptide (XX). The deprotection of (XX) by means of HCl yields dipeptide (XXI), which is condensed with intermediate (VI) by means of DEC and TEA to afford tripeptide (XXII). The deprotection of (XXII) by means of HBr yields tripeptide (XXIII), which is condensed with N-Boc-L-valine (XXIV) by means of BOPCl and TEA to afford tetrapeptide (XXV). The deprotection of (XXV) by means of HCl provides tetrapeptide (XXVI), which is finally condensed with N,N-dimethyl-L-valine (XXVII) by means of DEC and TEA to afford the target dolastatine.
| 【1】 Tomioka, K.; et al.; An expeditious synthesis of dolastatin 10. Tetrahedron 1991, 32, 21, 2395. |
| 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) | 54599 | (3R,4S)-4-[(tert-butoxycarbonyl)(methyl)amino]-3-methoxy-5-methylheptanoic acid | C15H29NO5 | 详情 | 详情 | |
| (XII) | 23520 | (2R,3R)-3-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-3-methoxy-2-methylpropionic acid | C14H25NO5 | 详情 | 详情 | |
| (XIX) | 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 | |
| (XX) | 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 | |
| (XXI) | 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 | |
| (XXII) | 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 | |
| (XXIII) | 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 | |
| (XXIV) | 19733 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid | C10H19NO4 | 详情 | 详情 | |
| (XXV) | 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 | |
| (XXVI) | 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 | |
| (XXVII) | 23518 | (2S)-2-(dimethylamino)-3-methylbutyric acid | C7H15NO2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XI)The reaction of the chiral oxazolidinone (I) with (Boc)2O gives the N-protected oxazolidinone (II), which is irradiated with UV light in acetonitrile in the presence of Bu3Sn-SnBu3 and the allylstannane (III) to yield the chiral 5-allyloxazolidinone (IV). Ring cleavage of (IV) by means of Cs2CO3 in methanol affords the N-protected aminoalcohol (V), which is treated with Ms-Cl and TEA in dichloromethane to provide the mesylate (VI). Epimerization of the O-Ms group of (VI) by means of Cs-OAc and 18-crown-6 in refluxing benzene gives the epimeric acetate (VII), which is hydrolyzed with K2CO3 in methanol to yield the N-protected aminoalcohol (VIII). The O-methylation of (VIII) by means of Me-I and Tl-OEt in THF affords the methyl ether (IX), which is N-methylated by means of Me-I and NaH in THF to provide the N-methyl carbamate (X). Finally, the terminal double bond of (X) is oxidated with RuCl3 and NaIO4 in CCl4/acetonitrile/water to furnish the target intermediate, the carboxylic acid (XI) (see scheme no. 149507a, intermediate (VIII)).
| 【1】 Kano, S.; et al.; Highly diastereoselective synthesis of N-Boc dolaisoleuine, unusual amino acid in dolastatin 10. Heterocycles 1990, 31, 9, 1597. |
| 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) | 54637 | (4S)-4-(sec-butyl)-5-(phenylsulfanyl)-1,3-oxazolidin-2-one | C13H17NO2S | 详情 | 详情 | |
| (II) | 54638 | tert-butyl (4S)-4-(sec-butyl)-2-oxo-5-(phenylsulfanyl)-1,3-oxazolidine-3-carboxylate | C18H25NO4S | 详情 | 详情 | |
| (III) | 40599 | Allyltributyltin; Tributyl-2-propenylstannane | 24850-33-7 | C15H32Sn | 详情 | 详情 |
| (IV) | 54639 | tert-butyl (4S,5S)-5-allyl-4-(sec-butyl)-2-oxo-1,3-oxazolidine-3-carboxylate | C15H25NO4 | 详情 | 详情 | |
| (V) | 54640 | tert-butyl (1S,2S)-1-(sec-butyl)-2-hydroxy-4-pentenylcarbamate | C14H27NO3 | 详情 | 详情 | |
| (VI) | 54641 | (1S)-1-{(1S)-1-[(tert-butoxycarbonyl)amino]-2-methylbutyl}-3-butenyl methanesulfonate | C15H29NO5S | 详情 | 详情 | |
| (VII) | 54642 | (1R)-1-{(1S)-1-[(tert-butoxycarbonyl)amino]-2-methylbutyl}-3-butenyl acetate | C16H29NO4 | 详情 | 详情 | |
| (VIII) | 54597 | tert-butyl (1S,2R)-1-(sec-butyl)-2-hydroxy-4-pentenylcarbamate | C14H27NO3 | 详情 | 详情 | |
| (IX) | 54643 | tert-butyl (1S,2R)-1-(sec-butyl)-2-methoxy-4-pentenylcarbamate | C15H29NO3 | 详情 | 详情 | |
| (X) | 54598 | tert-butyl (1S,2R)-1-(sec-butyl)-2-methoxy-4-pentenyl(methyl)carbamate | C16H31NO3 | 详情 | 详情 | |
| (XI) | 54599 | (3R,4S)-4-[(tert-butoxycarbonyl)(methyl)amino]-3-methoxy-5-methylheptanoic acid | C15H29NO5 | 详情 | 详情 |