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【结 构 式】

【药物名称】Dolastatin 10, NSC-376128, DLS-10

【化学名称】N,N-Dimethylvalyl-N-[2(R)-methoxy-4-[2(S)-[1(R)-methoxy-2(R)-methyl-3-oxo-3-[[2-phenyl-1(S)-(2-thiazolyl)ethyl]amino]propyl]-1-pyrrolidinyl]-1(S)-[1(S)-methylpropyl]-4-oxobutyl]-N-methylvalinamide

【CA登记号】110417-88-4

【 分 子 式 】C42H68N6O6S

【 分 子 量 】785.11086

【开发单位】University of Arizona (Originator), Abbott (Not Determined), Memorial Sloan-Kettering Cancer Center (Not Determined), National Cancer Institute (Codevelopment)

【药理作用】Breast Cancer Therapy, Leukemia Therapy, Lung Cancer Therapy, Lymphocytic Leukemia Therapy, Lymphoma Therapy, Non-Hodgkin's Lymphoma Therapy, Non-Small Cell Lung Cancer Therapy, Oncolytic Drugs, Solid Tumors Therapy, Antimitotic Drugs, Microtubule-Stabilizing Agents
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15

合成路线1

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).

参考文献 中间体
【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

The reaction of N-Boc-L-proline (IX) with O-methylhydroxylamine (II) gives the corresponding amide (X), which is reduced with LiAlH4 to N-Boc-L-prolinal (XI). The condensation of (XI) with boronate (XII) yields the carbinol (XIII) as the greater isomer, and it is methylated with Me-I and NaH to afford the methyl ether (XIV). Finally, the terminal double bond of (XIV) is oxidated by means of RuO4 to furnish the desired intermediate, the amino acid (XV).

参考文献 中间体
【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
(II) 46320 tert-butyl (2S)-2-[[methoxy(methyl)amino]carbonyl]-1-pyrrolidinecarboxylate C12H22N2O4 详情 详情
(IX) 16734 (2S)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-L-proline; (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid C10H17NO4 详情 详情
(X) 13361 (Methoxyamino)methane; N,O-Dimethylhydroxylamine 1117-97-1 C2H7NO 详情 详情
(XI) 16724 tert-Butyl (2S)-2-formyltetrahydro-1H-pyrrole-1-carboxylate; tert-Butoxycarbonyl-L-prolinal 69610-41-9 C10H17NO3 详情 详情
(XII) 54600 2-[(Z)-2-butenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane C10H19BO2 详情 详情
(XIII) 54601 tert-butyl (2S)-2-[(1R,2S)-1-hydroxy-2-methyl-3-butenyl]-1-pyrrolidinecarboxylate C14H25NO3 详情 详情
(XIV) 54602 tert-butyl (2S)-2-[(1R,2S)-1-methoxy-2-methyl-3-butenyl]-1-pyrrolidinecarboxylate C15H27NO3 详情 详情
(XV) 23520 (2R,3R)-3-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-3-methoxy-2-methylpropionic acid C14H25NO5 详情 详情

合成路线3

The reduction of N-(benzyloxycarbonyl)-L-phenylalanine (XVI) gives the corresponding aldehyde (XVII), which is cyclized with 2-sulfanylethylamine (XVIII) to yield the thiazolidine (XIX). The dehydrogenation of (XIX) by means of MnO2 affords the thiazole derivative (XX). Finally, the amino group of (XX) is deprotected with HBr to afford the desired intermediate, 2-phenyl-1(S)-(2-thiazolyl)ethylamine (XXI). Alternatively, N-(benzyloxycarbonyl)-L-phenylalanine (XVI) can be converted into the corresponding amide (XXII), which is treated with the Lawesson's reagent to yield the thioamide (XXIII). Finally, the cyclization of (XXIII) with 2-bromoacetaldehyde (XXIV) gives already reported thiazole derivative (XX) (partial racemization occurs during the synthetic process). Enantiomeric separation takes place in a later stage.

参考文献 中间体
【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
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
(XVI) 14505 (2S)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropionic acid; N-Carbobenzyloxy-L-phenylalanine; N-Cbz-L-Phenylalanine 1161-13-3 C17H17NO4 详情 详情
(XVII) 16586 benzyl N-[(1S)-1-benzyl-2-oxoethyl]carbamate C17H17NO3 详情 详情
(XVIII) 13186 2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine 60-23-1 C2H7NS 详情 详情
(XX) 54604 benzyl (1S)-2-phenyl-1-(1,3-thiazolidin-2-yl)ethylcarbamate C19H22N2O2S 详情 详情
(XXI) 24802 2-bromoacetaldehyde C2H3BrO 详情 详情
(XXII) 54603 benzyl (1S)-2-amino-1-benzyl-2-oxoethylcarbamate 4801-80-3 C17H18N2O3 详情 详情
(XXIII) 54605 benzyl (1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethylcarbamate C19H18N2O2S 详情 详情
(XXIV) 54606 benzyl (1S)-2-amino-1-benzyl-2-thioxoethylcarbamate C17H18N2O2S 详情 详情

合成路线4

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.

参考文献 中间体
【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5

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.

参考文献 中间体
【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6

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).

参考文献 中间体
【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7

The reaction of N-Boc-L-prolinal (VII) with the boron enolate (VIII) in ethyl ether gives the chiral beta-hydroxythioester (IX), which is transesterified with K2CO3 and ethanol to afford the beta-hydroxypropionate (X). The methylation of the OH group of (X) with LiHMDS and Me-OTf as before provides the methoxyester (XI), which is finally hydrolyzed with LiOH in aq. ethanol to furnish the desired intermediate, the methoxy amino acid (XII).

参考文献 中间体
【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
(VII) 16734 (2S)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-L-proline; (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid C10H17NO4 详情 详情
(VIII) 54620 9-{[(E)-1-(phenylsulfanyl)-1-propenyl]oxy}-9-borabicyclo[3.3.1]nonane; (E)-1-(9-borabicyclo[3.3.1]non-9-yloxy)-1-propenyl phenyl sulfide C17H23BOS 详情 详情
(IX) 54621 tert-butyl (2S)-2-[(1R,2R)-1-hydroxy-2-methyl-3-oxo-3-(phenylsulfanyl)propyl]-1-pyrrolidinecarboxylate C19H27NO4S 详情 详情
(X) 54622 tert-butyl (2S)-2-[(1R,2R)-3-ethoxy-1-hydroxy-2-methyl-3-oxopropyl]-1-pyrrolidinecarboxylate C15H27NO5 详情 详情
(XI) 54623 tert-butyl (2S)-2-[(1R,2R)-3-ethoxy-1-methoxy-2-methyl-3-oxopropyl]-1-pyrrolidinecarboxylate C16H29NO5 详情 详情
(XII) 23520 (2R,3R)-3-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-3-methoxy-2-methylpropionic acid C14H25NO5 详情 详情

合成路线8

The reduction of N-Boc-L-phenylalanine (XIII) with B2H6 in THF gives the expected alcohol (XIV), which is oxidized with SO3/pyridine to yield the corresponding aldehyde (XV). The cyclization of (XV) with 2-sulfanylethylamine (XVI) affords the thiazolidine (XVII), which is dehydrogenated by means of MnO2 to afford the thiazole derivative (XVIII). Finally, the amino group of (XVIII) is deprotected with HCl to afford the desired intermediate, 2-phenyl-1(S)-(2-thiazolyl)ethylamine (XIX).

参考文献 中间体
【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
(XIII) 12874 (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine 13734-34-4 C14H19NO4 详情 详情
(XIV) 54624 tert-butyl (1S)-1-benzyl-2-hydroxyethylcarbamate C14H21NO3 详情 详情
(XV) 23452 tert-butyl (1S)-1-benzyl-2-oxoethylcarbamate C14H19NO3 详情 详情
(XVI) 13186 2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine 60-23-1 C2H7NS 详情 详情
(XVII) 54625 tert-butyl (1S)-2-phenyl-1-(1,3-thiazolidin-2-yl)ethylcarbamate C16H24N2O2S 详情 详情
(XVIII) 54626 tert-butyl (1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethylcarbamate C16H20N2O2S 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

合成路线9

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.

参考文献 中间体
【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10

The methylation of N-(benzyloxycarbonyl)-L-isoleucine (I) with Me-I and NaH in THF gives the N-methyl derivative (II), which is reduced with BH3 in THF to yield the isoleucinol (III). The oxidation of (III) with SO3/pyridine in DMSO affords the isoleucinal (IV), which is condensed with tert-butyl acetate (V) by means of BuLi and THF to afford the chiral beta-hydroxyheptanoate (VI). Finally, this compound is O-methylated by means of diazomethane and BF3 in ethyl ether/dichloromethane and N-deprotected by hydrogenation with H2 over Pd/C in ethyl acetate/methanol to provide the desired intermediate, the chiral tert-butyl heptanoate (VII).

参考文献 中间体
【1】 Pettit, G.R.; Singh, S.B.; Williams, M.D.; Herald, D.L.; Hogan, F.; Burkett, D.D.; Clewlow, P.J.; The absolute configuration and synthesis of natural (-)-Dolastatin 10. J Am Chem Soc 1989, 111, Suppl. 3, 5463.
【2】 Pettit, G.R.; Srirangam, J.K.; Singh, S.B.; Williams, M.D.; Herald, D.L.; Barkóczy, J.; Kantoci, D.; Hogan, F.; Dolastatins 24. Synthesis of (-)-dolastatin 10. X-Ray molecular structure of N,N-dimethylvalyl-valyl-dolaisoleucine tert-butyl ester. J Chem Soc Perkins Trans I 1996, 8, Suppl. 3, 859-63.
【3】 Pettit, G.R.; Singh, S.B. (Arizona State University); Synthesis of dolastatin 10. US 4978744 .
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) 23508 (2S,3S)-2-[[(benzyloxy)carbonyl]amino]-3-methylpentanoic acid 3160-59-6 C14H19NO4 详情 详情
(II) 54627 (2S,3S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-methylpentanoic acid C15H21NO4 详情 详情
(III) 54628 benzyl (1S,2S)-1-(hydroxymethyl)-2-methylbutyl(methyl)carbamate C15H23NO3 详情 详情
(IV) 54629 benzyl (1S,2S)-1-formyl-2-methylbutyl(methyl)carbamate C15H21NO3 详情 详情
(V) 13597 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride 3282-30-2 C5H9ClO 详情 详情
(VI) 54630 tert-butyl (3R,4S,5S)-4-[[(benzyloxy)carbonyl](methyl)amino]-3-hydroxy-5-methylheptanoate C21H33NO5 详情 详情
(VII) 23514 tert-butyl (3R,4S,5S)-3-methoxy-5-methyl-4-(methylamino)heptanoate C14H29NO3 详情 详情

合成路线11

The reaction of L-prolinol (VIII) with Boc2O gives N-Boc-L-prolinol (IX), which is oxidized with SO3/pyridine in DMSO to afford N-Boc-L-prolinal (X). The condensation of (X) with the propionate ester (XI), by means of LDA in THF, affords the 3-hydroxy-3-(2-pyrrolidinyl)propionate ester (XII), which is methylated with diazomethane and BF3 in dichloromethane to provide the corresponding methoxy derivative (XIII). The epimerization of the (S)-methyl group of group of (XIII) by means of t-Bu-OK in THF gives the corresponding (R)-methyl derivative (XIV), which is finally hydrogenolyzed with H2 over Pd/C in ethyl acetate/methanol to yield the desired pyrrolidinylpropionic acid intermediate (XV).

参考文献 中间体
【1】 Pettit, G.R.; Singh, S.B.; Williams, M.D.; Herald, D.L.; Hogan, F.; Burkett, D.D.; Clewlow, P.J.; The absolute configuration and synthesis of natural (-)-Dolastatin 10. J Am Chem Soc 1989, 111, Suppl. 3, 5463.
【2】 Pettit, G.R.; Srirangam, J.K.; Singh, S.B.; Williams, M.D.; Herald, D.L.; Barkóczy, J.; Kantoci, D.; Hogan, F.; Dolastatins 24. Synthesis of (-)-dolastatin 10. X-Ray molecular structure of N,N-dimethylvalyl-valyl-dolaisoleucine tert-butyl ester. J Chem Soc Perkins Trans I 1996, 8, Suppl. 3, 859-63.
【3】 Pettit, G.R.; Singh, S.B. (Arizona State University); Synthesis of dolastatin 10. US 4978744 .
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) 21347 (2S)pyrrolidinylmethanol 23356-96-9 C5H11NO 详情 详情
(IX) 49819 (S)-1-(tert-Butoxycarbonyl)-2-pyrrolidinenemethanol C10H19NO3 详情 详情
(X) 16724 tert-Butyl (2S)-2-formyltetrahydro-1H-pyrrole-1-carboxylate; tert-Butoxycarbonyl-L-prolinal 69610-41-9 C10H17NO3 详情 详情
(XI) 54631 (1S)-2-hydroxy-1,2,2-triphenylethyl propionate C23H22O3 详情 详情
(XII) 54632 tert-butyl (2S)-2-((1R,2S)-1-hydroxy-3-{[(1S)-2-hydroxy-1,2,2-triphenylethyl]oxy}-2-methyl-3-oxopropyl)-1-pyrrolidinecarboxylate C33H39NO6 详情 详情
(XIII) 54633 tert-butyl (2S)-2-((1R,2S)-3-{[(1S)-2-hydroxy-1,2,2-triphenylethyl]oxy}-1-methoxy-2-methyl-3-oxopropyl)-1-pyrrolidinecarboxylate C34H41NO6 详情 详情
(XIV) 54634 tert-butyl (2S)-2-((1R,2R)-3-{[(1S)-2-hydroxy-1,2,2-triphenylethyl]oxy}-1-methoxy-2-methyl-3-oxopropyl)-1-pyrrolidinecarboxylate C34H41NO6 详情 详情
(XV) 23520 (2R,3R)-3-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-3-methoxy-2-methylpropionic acid C14H25NO5 详情 详情

合成路线12

The reduction of N-Boc-L-phenylalanine (XVI) with diborane in THF gives N-Boc-L-phenylalaninol (XVII), which is oxidized with SO3/pyridine in DMSO to yield N-Boc-L-phenylalaninal (XVIII). The cyclization of (XVIII) with 2-sulfanylethylamine (XIX) affords the thiazolidine (XX), which is dehydrogenated by means of MnO2 to provide the thiazole derivative (XXI). Finally, compound (XXI) is N-deprotected by a treatment with TFA to provide the 2-phenyl-1(S)-(2-thiazolyl)ethylamine intermediate (XXII).

参考文献 中间体
【1】 Pettit, G.R.; Srirangam, J.K.; Singh, S.B.; Williams, M.D.; Herald, D.L.; Barkóczy, J.; Kantoci, D.; Hogan, F.; Dolastatins 24. Synthesis of (-)-dolastatin 10. X-Ray molecular structure of N,N-dimethylvalyl-valyl-dolaisoleucine tert-butyl ester. J Chem Soc Perkins Trans I 1996, 8, Suppl. 3, 859-63.
【2】 Pettit, G.R.; Singh, S.B.; Williams, M.D.; Herald, D.L.; Hogan, F.; Burkett, D.D.; Clewlow, P.J.; The absolute configuration and synthesis of natural (-)-Dolastatin 10. J Am Chem Soc 1989, 111, Suppl. 3, 5463.
【3】 Pettit, G.R.; Singh, S.B. (Arizona State University); Synthesis of dolastatin 10. US 4978744 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVI) 12874 (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine 13734-34-4 C14H19NO4 详情 详情
(XVII) 54624 tert-butyl (1S)-1-benzyl-2-hydroxyethylcarbamate C14H21NO3 详情 详情
(XVIII) 23452 tert-butyl (1S)-1-benzyl-2-oxoethylcarbamate C14H19NO3 详情 详情
(XIX) 13186 2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine 60-23-1 C2H7NS 详情 详情
(XX) 54625 tert-butyl (1S)-2-phenyl-1-(1,3-thiazolidin-2-yl)ethylcarbamate C16H24N2O2S 详情 详情
(XXI) 54626 tert-butyl (1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethylcarbamate C16H20N2O2S 详情 详情
(XXII) 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

合成路线13

The condensation of N-(benzyloxycarbonyl)-L-valine (XXIII) with intermediate heptanoate (VII) by means of NMM and Piv-Cl gives the dipeptide (XXIV), which is N-deprotected by means of H2 over Pd/C to yield the dipeptide (XXV). The condensation of (XXV) with N,N-dimethyl-L-valine (XXVI) (obtained by reductomethylation of L-valine (XXVII) with formaldehyde and H2 over Pd/C) by means of pentafluorophenyl trifluoroacetate and TFAA in pyridine affords the tripeptide (XXVIII), which is treated with TFA to cleave the tert-butyl group, yielding the tripeptide (XXIX). The condensation of (XXIX) with intermediate dipeptide (XXX) by means of DEPC provides the target pentapeptide dolastatin 10. The intermediate dipeptide (XXX) is obtained by condensation of intermediate (XV) with intermediate (XXII) by means of DEPC to give the dipeptide (XXXI), which is N-deprotected by treatment with TFA to afford the desired dipeptide (XXX).

参考文献 中间体
【1】 Pettit, G.R.; Singh, S.B.; Williams, M.D.; Herald, D.L.; Hogan, F.; Burkett, D.D.; Clewlow, P.J.; The absolute configuration and synthesis of natural (-)-Dolastatin 10. J Am Chem Soc 1989, 111, Suppl. 3, 5463.
【2】 Pettit, G.R.; Srirangam, J.K.; Singh, S.B.; Williams, M.D.; Herald, D.L.; Barkóczy, J.; Kantoci, D.; Hogan, F.; Dolastatins 24. Synthesis of (-)-dolastatin 10. X-Ray molecular structure of N,N-dimethylvalyl-valyl-dolaisoleucine tert-butyl ester. J Chem Soc Perkins Trans I 1996, 8, Suppl. 3, 859-63.
【3】 Pettit, G.R.; Singh, S.B. (Arizona State University); Synthesis of dolastatin 10. US 4978744 .
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) 23514 tert-butyl (3R,4S,5S)-3-methoxy-5-methyl-4-(methylamino)heptanoate C14H29NO3 详情 详情
(XV) 23520 (2R,3R)-3-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-3-methoxy-2-methylpropionic acid C14H25NO5 详情 详情
(XXII) 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
(XXIII) 18092 (2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutyric acid C13H17NO4 详情 详情
(XXIV) 23516 tert-butyl (3R,4S,5S)-4-[((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)(methyl)amino]-3-methoxy-5-methylheptanoate C27H44N2O6 详情 详情
(XXV) 23517 tert-butyl (3R,4S,5S)-4-[[(2S)-2-amino-3-methylbutanoyl](methyl)amino]-3-methoxy-5-methylheptanoate C19H38N2O4 详情 详情
(XXVI) 23518 (2S)-2-(dimethylamino)-3-methylbutyric acid C7H15NO2 详情 详情
(XXVII) 21056 (R)-(-)-Valine; D-Valine; (R)-alpha-Aminoisovaleric acid 640-68-6 C5H11NO2 详情 详情
(XXVIII) 23519 tert-butyl (3R,4S,5S)-4-[((2S)-2-[[(2S)-2-(dimethylamino)-3-methylbutanoyl]amino]-3-methylbutanoyl)(methyl)amino]-3-methoxy-5-methylheptanoate C26H51N3O5 详情 详情
(XXIX) 23505 (3R,4S,5S)-4-[((2S)-2-[[(2S)-2-(dimethylamino)-3-methylbutanoyl]amino]-3-methylbutanoyl)(methyl)amino]-3-methoxy-5-methylheptanoic acid C22H43N3O5 详情 详情
(XXX) 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
(XXXI) 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

合成路线14

The enantioselective condensation of N-Boc-L-prolinal (I) with the chiral 2-bromopropionyloxazolidinone (II) by means of Co(PPh3)4 in THF gives the chiral beta-hydroxyamide (III), which is methylated by means of trimethyloxonium tetrafluoroborate in dichloromethane to yield the methyl ether (IV). Finally, elimination of the chiral auxiliary of (IV) by means of LiOH and H2O2 affords the target amino acid intermediate (V) (see scheme no. 14950701a , intermediate (XV)).

参考文献 中间体
【1】 Pettit, G.R.; Grealish, M.P.; A cobalt-phosphine complex directed reformatsky approach to a stereospecific synthesis of the dolastatin 10 unit dolaproine (Dap). J Org Chem 2001, 66, 25, 8640.
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) 16734 (2S)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-L-proline; (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid C10H17NO4 详情 详情
(II) 54635 (4R,5S)-3-(2-bromopropanoyl)-4-methyl-5-phenyl-1,3-oxazolidin-2-one C13H14BrNO3 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) 54636 tert-butyl (2S)-2-{(1R,2R)-1-methoxy-2-methyl-3-[(4R,5S)-4-methyl-2-oxo-5-phenyl-1,3-oxazolidin-3-yl]-3-oxopropyl}-1-pyrrolidinecarboxylate C24H34N2O6 详情 详情
(V) 23520 (2R,3R)-3-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-3-methoxy-2-methylpropionic acid C14H25NO5 详情 详情

合成路线15

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)).

参考文献 中间体
【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
Extended Information