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【结 构 式】 
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【分子编号】23508 【品名】(2S,3S)-2-[[(benzyloxy)carbonyl]amino]-3-methylpentanoic acid 【CA登记号】3160-59-6 |
【 分 子 式 】C14H19NO4 【 分 子 量 】265.3092 【元素组成】C 63.38% H 7.22% N 5.28% O 24.12% |
合成路线1
该中间体在本合成路线中的序号：(I)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).
| 【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2
该中间体在本合成路线中的序号：(III)Title compound was prepared by two related ways: N-(Benzyloxycarbonyl)-L-tryptofanol (I) was deprotected by hydrogenolysis in the presence of Pd/C. The resulting tryptofanol (II) was then coupled with N-(benzyloxycarbonyl)-L-isoleucine (III), using 1-(3-diethylaminopropyl)-3-ethylcarbodiimide.HCl (EDC) and 1-hydroxybenzotriazole (HOBt) to provide (IV). Subsequent hydrogenolytic deprotection gave amine (V), which was condensed with 1-naphthalenylsulfonyl chloride (VI) in the presence of 4-(dimethylamino)pyridine to afford sulfonamide (VII). Finally, oxidation with DMSO in the presence of SO3-pyridine complex yielded the aldehyde.
| 【1】 Yasuma, T.; Oi, S.; Choh, N.; Nomura, T.; Furuyama, N.; Nishimura, A.; Fujisawa, Y.; Sohda, T.; Synthesis of peptide aldehyde derivatives as selective inhibitors of human cathepsin L and their inhibitory effect on bone resorption. J Med Chem 1998, 41, 22, 4301. |
| 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) | 18645 | benzyl (1S)-2-hydroxy-1-(1H-indol-3-ylmethyl)ethylcarbamate | C19H20N2O3 | 详情 | 详情 | |
| (II) | 18646 | (2S)-2-amino-3-(1H-indol-3-yl)-1-propanol | C11H14N2O | 详情 | 详情 | |
| (III) | 23508 | (2S,3S)-2-[[(benzyloxy)carbonyl]amino]-3-methylpentanoic acid | 3160-59-6 | C14H19NO4 | 详情 | 详情 |
| (IV) | 18648 | benzyl (1S,2S)-1-([[(1S)-2-hydroxy-1-(1H-indol-3-ylmethyl)ethyl]amino]carbonyl)-2-methylbutylcarbamate | C25H31N3O4 | 详情 | 详情 | |
| (V) | 18649 | (2S,3S)-2-amino-N-[(1S)-2-hydroxy-1-(1H-indol-3-ylmethyl)ethyl]-3-methylpentanamide | C17H25N3O2 | 详情 | 详情 | |
| (VI) | 18650 | 1-naphthalenesulfonyl chloride | 85-46-1 | C10H7ClO2S | 详情 | 详情 |
| (VII) | 18651 | (2S,3S)-N-[(1S)-2-hydroxy-1-(1H-indol-3-ylmethyl)ethyl]-3-methyl-2-[(1-naphthylsulfonyl)amino]pentanamide | C27H31N3O4S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)Alternatively, N-(benzyloxycarbonyl)-L-Trp (VIII) was condensed with N,O-dimethylhydroxylamine in the presence of EDC and HOBt to give N-(methoxy)amide (IX). Hydrogenolytic deprotection produced amine (X), which was coupled with Z-Ile (III) to afford dipeptide (XI). Subsequent deprotection, and coupling of the resulting amine (XII) with sulfonyl chloride (VI) gave sulfonamide (XIII). Then, reduction of the N-(methoxy)amide with diisobutylaluminum hydride furnished the target aldehyde
| 【1】 Yasuma, T.; Oi, S.; Choh, N.; Nomura, T.; Furuyama, N.; Nishimura, A.; Fujisawa, Y.; Sohda, T.; Synthesis of peptide aldehyde derivatives as selective inhibitors of human cathepsin L and their inhibitory effect on bone resorption. J Med Chem 1998, 41, 22, 4301. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 23508 | (2S,3S)-2-[[(benzyloxy)carbonyl]amino]-3-methylpentanoic acid | 3160-59-6 | C14H19NO4 | 详情 | 详情 |
| (VI) | 18650 | 1-naphthalenesulfonyl chloride | 85-46-1 | C10H7ClO2S | 详情 | 详情 |
| (VIII) | 18652 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-(1H-indol-3-yl)propionic acid | 7432-21-5 | C19H18N2O4 | 详情 | 详情 |
| (IX) | 18653 | benzyl (1S)-1-(1H-indol-3-ylmethyl)-2-[methoxy(methyl)amino]-2-oxoethylcarbamate | C21H23N3O4 | 详情 | 详情 | |
| (X) | 18654 | (2S)-2-amino-3-(1H-indol-3-yl)-N-methoxy-N-methylpropanamide | C13H17N3O2 | 详情 | 详情 | |
| (XI) | 18655 | benzyl (1S,2S)-1-[([(1S)-1-(1H-indol-3-ylmethyl)-2-[methoxy(methyl)amino]-2-oxoethyl]amino)carbonyl]-2-methylbutylcarbamate | C27H34N4O5 | 详情 | 详情 | |
| (XII) | 18656 | (2S,3S)-2-amino-N-[(1S)-1-(1H-indol-3-ylmethyl)-2-[methoxy(methyl)amino]-2-oxoethyl]-3-methylpentanamide | C19H28N4O3 | 详情 | 详情 | |
| (XIII) | 18657 | (2S,3S)-N-[(1S)-1-(1H-indol-3-ylmethyl)-2-[methoxy(methyl)amino]-2-oxoethyl]-3-methyl-2-[(1-naphthylsulfonyl)amino]pentanamide | C29H34N4O5S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IX)Intermediate (VI) has been obtained as follows: The condensation of benzyloxycarbonyl-L-isoleucine (IX) with malonic acid monomethyl ester potassium salt (X) by means of carbonyldiimidazole (CDI) and MgCl2 in THF gives the ketoester (XI), which is reduced to the hydroxyester (XII) with NaBH4 in methanol. The methylation of (XII) with methyl iodide and silver oxide in DMF affords the N-methyl methoxyester (XIII). The hydrolysis of (XIII) with NaOH in dioxane/water followed by reesterification with isobutylene gives the tert-butyl ester (XIV), which is deprotected by hydrogenation over Pd/C, yielding the amino acid (XV). The condensation of (XV) with benzyloxycarbonyl-L-valine (XVI) by means of DCC in dichloromethane gives the protected dipeptide (XVII), which is debenzylated as usual, yielding (XVIII). The condensation of (XVIII) with N,N-dimethyl-L-valine (XIX) affords the tripeptide ter-butyl ester (XX). Finally, (XX) is hydrolyzed by treatment with trifluoroacetic acid to the free acid intermediate (VI).
| 【1】 Tsukagoshi, S.; Sakakibara, K.; Gondo, M.; Natsume, T.; Mikami, T.; Kobayashi, M.; Miyazaki, K.; Synthesis and antitumor activity of novel dolastat. Chem Pharm Bull 1995, 43, 10, 1706. |
| 【2】 Castañer, J.; Leeson, P.; Hoshi, A.; TZT-1027. Drugs Fut 1999, 24, 4, 404. |
| 【3】 Sakakibara, K.; Gondo, M.; Miyazaki, K. (Teikoku Hormone Manufacturing Co., Ltd.); Novel tetrapeptide derivs.. EP 0598129; JP 1993503479; US 5654399; WO 9303054 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15926 | 2-methyl-1-propene; isobutylene | 115-11-7 | C4H8 | 详情 | 详情 | |
| (VI) | 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 | |
| (IX) | 23508 | (2S,3S)-2-[[(benzyloxy)carbonyl]amino]-3-methylpentanoic acid | 3160-59-6 | C14H19NO4 | 详情 | 详情 |
| (X) | 23509 | 3-methoxy-3-oxopropanoate | C4H5O4 | 详情 | 详情 | |
| (XI) | 23510 | methyl (4S,5S)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-oxoheptanoate | C17H23NO5 | 详情 | 详情 | |
| (XII) | 23511 | methyl (3R,4S,5S)-4-[[(benzyloxy)carbonyl]amino]-3-hydroxy-5-methylheptanoate | C17H25NO5 | 详情 | 详情 | |
| (XIII) | 23512 | methyl (3R,4S,5S)-4-[[(benzyloxy)carbonyl](methyl)amino]-3-methoxy-5-methylheptanoate | C19H29NO5 | 详情 | 详情 | |
| (XIV) | 23513 | tert-butyl (3R,4S,5S)-4-[[(benzyloxy)carbonyl](methyl)amino]-3-methoxy-5-methylheptanoate | C22H35NO5 | 详情 | 详情 | |
| (XV) | 23514 | tert-butyl (3R,4S,5S)-3-methoxy-5-methyl-4-(methylamino)heptanoate | C14H29NO3 | 详情 | 详情 | |
| (XVI) | 18092 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutyric acid | C13H17NO4 | 详情 | 详情 | |
| (XVII) | 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 | |
| (XVIII) | 23517 | tert-butyl (3R,4S,5S)-4-[[(2S)-2-amino-3-methylbutanoyl](methyl)amino]-3-methoxy-5-methylheptanoate | C19H38N2O4 | 详情 | 详情 | |
| (XIX) | 23518 | (2S)-2-(dimethylamino)-3-methylbutyric acid | C7H15NO2 | 详情 | 详情 | |
| (XX) | 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 |
合成路线5
该中间体在本合成路线中的序号：(II)Protection of D-alloisoleucine (I) with Cbz-succinimide afforded benzyl carbamate (II). Activation of the carboxyl group of (II) as the pentafluorophenyl ester (III), followed by condensation with the lithium enolate of methyl acetate, gave beta-ketoester (IV). Stereoselective reduction of (IV) with KBH4 produced alcohol (V) as the major diastereomer. The hydroxyl group of (V) was protected as the triisopropylsilyl ether (VI), and then hydrolysis of the ester group of (VI) yielded carboxylic acid (VII).
| 【1】 Liang, B.; et al.; The first total synthesis of (-)-tamadarin A. Org Lett 1999, 1, 8, 1319. |
| 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) | 32739 | L-2-Amino-3-methylpentanoic acid; L-isoleucine | 73-32-5 | C6H13NO2 | 详情 | 详情 |
| (II) | 23508 | (2S,3S)-2-[[(benzyloxy)carbonyl]amino]-3-methylpentanoic acid | 3160-59-6 | C14H19NO4 | 详情 | 详情 |
| (III) | 37824 | 2,3,4,5,6-pentafluorophenyl (2S,3S)-2-[[(benzyloxy)carbonyl]amino]-3-methylpentanoate | C20H18F5NO4 | 详情 | 详情 | |
| (IV) | 23510 | methyl (4S,5S)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-oxoheptanoate | C17H23NO5 | 详情 | 详情 | |
| (V) | 37825 | methyl (3S,4S,5S)-4-[[(benzyloxy)carbonyl]amino]-3-hydroxy-5-methylheptanoate | C17H25NO5 | 详情 | 详情 | |
| (VI) | 37826 | methyl (3S,4S,5S)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]heptanoate | C26H45NO5Si | 详情 | 详情 | |
| (VII) | 37827 | (3S,4S,5S)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]heptanoic acid | C25H43NO5Si | 详情 | 详情 |