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【结 构 式】 
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【分子编号】63790 【品名】methyl (4R,6S)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-({2-[(Z)-3-(tetrahydro-2H-pyran-2-yloxy)-1-propenyl]anilino}carbothioyl)-6-{[(triethylsilyl)oxy]methyl}-6-[(trimethylsilyl)oxy]octanoate 【CA登记号】 |
【 分 子 式 】C51H79NO7SSi3 【 分 子 量 】934.5133 【元素组成】C 65.55% H 8.52% N 1.5% O 11.98% S 3.43% Si 9.02% |
合成路线1
该中间体在本合成路线中的序号：(XXXVIII)4-Ethylpent-4-enoic acid (XXIV) is coupled to (R)-4-benzyl-2-oxazolidinone (XXV) via its mixed anhydride with pivaloyl chloride, producing the N-acyl oxazolidinone (XXVI). Diastereoselective cyanoethylation of (XXVI) with acrylonitrile leads to (XXVII). Reduction of imide (XXVII) with NaBH4, followed by protection of the resulting alcohol with t-butyldiphenylsilyl chloride furnishes the silyl ether (XXVIII). The nitrile function of (XXVIII) is then reduced by means of DIBAL to the aldehyde (XXIX), which is further treated with hydroxylamine to yield the corresponding oxime (XXX). Exposure of oxime (XXX) to NaOCl generates an intermediate nitrile oxide, which undergoes intramolecular 1,3-dipolar cycloaddition to the isoxazoline (XXXI). Subsequent reductive cleavage of the isoxazoline (XXXI) N-O bond with Zn/AcOH leads to compound (XXXII). Cyclohexanone (XXXII) is then converted to lactone (XXXIII) under Baeyer-Villiger conditions. Further methanolysis of lactone (XXXIII) gives rise to the open-chain dihydroxyester (XXXIV). Sequential protection of the primary hydroxyl group with triethylchlorosilane and the tertiary hydroxyl with trimethylchlorosilane furnishes the fully silylated triol (XXXV) (8). The lithium enolate of ester (XXXV) is then condensed with isothiocyanate (XXXVI) to produce thioanilide (XXXVII) (8, 9).
| 【1】 Yokoshima, S.; Ueda, T.; Kobayashi, S.; Sato, A.; Kuboyama, T.; Tokuyama, H.; Fukuyama, T.; Stereocontrolled total synthesis of (+)-vinblastine. J Am Chem Soc 2002, 124, 10, 2137. |
| 【2】 Schneider, C.; First de novo synthesis of the bisindole alkaloid vinblastine. Angew Chem. Int Ed 2002, 41, 22, 4217. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXV) | 63776 | 4-ethyl-4-pentenoic acid | C7H12O2 | 详情 | 详情 | |
| (XXVI) | 14694 | (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone | 90719-32-7 | C10H11NO2 | 详情 | 详情 |
| (XXVII) | 63777 | (4R)-4-benzyl-3-(4-ethyl-4-pentenoyl)-1,3-oxazolidin-2-one | C17H21NO3 | 详情 | 详情 | |
| (XXVIII) | 63778 | (4R)-4-{[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}-6-ethyl-6-heptenenitrile | C20H24N2O3 | 详情 | 详情 | |
| (XXIX) | 63780 | (4R)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-ethyl-6-heptenenitrile | C26H35NOSi | 详情 | 详情 | |
| (XXX) | 63779 | (4R)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-ethyl-6-heptenal | C26H36O2Si | 详情 | 详情 | |
| (XXXI) | 63781 | (4R)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-ethyl-6-heptenal oxime | C26H37NO2Si | 详情 | 详情 | |
| (XXXII) | 63782 | (3aR,5R)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3a-ethyl-3,3a,4,5,6,7-hexahydro-2,1-benzisoxazole; [(3aR,5R)-3a-ethyl-3,3a,4,5,6,7-hexahydro-2,1-benzisoxazol-5-yl]methyl tert-butyl(diphenyl)silyl ether | C26H35NO2Si | 详情 | 详情 | |
| (XXXIII) | 63783 | (2S,4R)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-ethyl-2-(hydroxymethyl)cyclohexanone | C26H36O3Si | 详情 | 详情 | |
| (XXXIV) | 63784 | (5R,7S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-7-ethyl-7-(hydroxymethyl)-2-oxepanone | C26H36O4Si | 详情 | 详情 | |
| (XXXV) | 63785 | methyl (4R,6S)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-hydroxy-6-(hydroxymethyl)octanoate | C27H40O5Si | 详情 | 详情 | |
| (XXXVI) | 63788 | methyl (4R,6S)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-{[(triethylsilyl)oxy]methyl}-6-[(trimethylsilyl)oxy]octanoate | C36H62O5Si3 | 详情 | 详情 | |
| (XXXVII) | 63789 | 2-[(Z)-3-(tetrahydro-2H-pyran-2-yloxy)-1-propenyl]phenyl isothiocyanate; 2-{[(Z)-3-(2-isothiocyanatophenyl)-2-propenyl]oxy}tetrahydro-2H-pyran | C15H17NO2S | 详情 | 详情 | |
| (XXXVIII) | 63790 | methyl (4R,6S)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-({2-[(Z)-3-(tetrahydro-2H-pyran-2-yloxy)-1-propenyl]anilino}carbothioyl)-6-{[(triethylsilyl)oxy]methyl}-6-[(trimethylsilyl)oxy]octanoate | C51H79NO7SSi3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXXVIII)Radical cyclization of thioanilide (XXXVII) gives rise to indole (XXXVIII), which is further protected as the N-Boc derivative (XXXIX) employing Boc2O. The fully protected tr (XXXIX) is then treated with 95% AcOH to furnish triol (XL). Upon treatment of triol (XL) with tosyl chloride and triethylamine in the presence of dibutyltin oxide, tosylation occurs selectively at the primary alcohol of the 1,2-diol moiety. The resulting tosylate (XLI) is further cyclized to epoxide (XLII) in the presence of NaHCO3 in hot DMF. The remaining primary alcohol of (XLIII) is then coupled to p-nitrobenzenesulfonamide (XLIII) under Mitsunobu conditions, producing (XLIV). Macrocyclization of the epoxy sulfonamide (XLIV) upon heating with K2CO3 in DMF yields the 11-membered ring compound (XLV) (8,9).
| 【1】 Schneider, C.; First de novo synthesis of the bisindole alkaloid vinblastine. Angew Chem. Int Ed 2002, 41, 22, 4217. |
| 【2】 Yokoshima, S.; Ueda, T.; Kobayashi, S.; Sato, A.; Kuboyama, T.; Tokuyama, H.; Fukuyama, T.; Stereocontrolled total synthesis of (+)-vinblastine. J Am Chem Soc 2002, 124, 10, 2137. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXVIII) | 63790 | methyl (4R,6S)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-({2-[(Z)-3-(tetrahydro-2H-pyran-2-yloxy)-1-propenyl]anilino}carbothioyl)-6-{[(triethylsilyl)oxy]methyl}-6-[(trimethylsilyl)oxy]octanoate | C51H79NO7SSi3 | 详情 | 详情 | |
| (XXXIX) | 63810 | methyl (4R,6S)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-{3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-indol-2-yl}-6-{[(triethylsilyl)oxy]methyl}-6-[(trimethylsilyl)oxy]octanoate | C51H79NO7Si3 | 详情 | 详情 | |
| (XL) | 63811 | tert-butyl 2-{(3R,5S)-3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-1-(methoxycarbonyl)-5-{[(triethylsilyl)oxy]methyl}-5-[(trimethylsilyl)oxy]heptyl}-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-indole-1-carboxylate | C56H87NO9Si3 | 详情 | 详情 | |
| (XLI) | 63812 | tert-butyl 2-[(3R,5S)-3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-hydroxy-5-(hydroxymethyl)-1-(methoxycarbonyl)heptyl]-3-(2-hydroxyethyl)-1H-indole-1-carboxylate | C42H57NO8Si | 详情 | 详情 | |
| (XLII) | 63813 | tert-butyl 2-[(3R,5S)-3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-hydroxy-1-(methoxycarbonyl)-5-({[(4-methylphenyl)sulfonyl]oxy}methyl)heptyl]-3-(2-hydroxyethyl)-1H-indole-1-carboxylate | C49H63NO10SSi | 详情 | 详情 | |
| (XLIII) | 63814 | tert-butyl 2-[(3R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-{[(2S)-2-ethyloxiranyl]methyl}-1-(methoxycarbonyl)butyl]-3-(2-hydroxyethyl)-1H-indole-1-carboxylate | C42H55NO7Si | 详情 | 详情 | |
| (XLIV) | 55807 | 4-Nitrobenzenesulfonamide; p-Nitrobenzenesulfonamide | 6325-93-5 | C6H6N2O4S | 详情 | 详情 |
| (XLV) | 63815 | tert-butyl 2-[(3R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-{[(2S)-2-ethyloxiranyl]methyl}-1-(methoxycarbonyl)butyl]-3-(2-{[(4-nitrophenyl)sulfonyl]amino}ethyl)-1H-indole-1-carboxylate | C48H59N3O10SSi | 详情 | 详情 | |
| (XLVI) | 63816 | 10-(tert-butyl) 9-methyl (5S,7R)-7-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-ethyl-5-hydroxy-3-[(4-nitrophenyl)sulfonyl]-2,3,4,5,6,7,8,9-octahydroazacycloundecino[5,4-b]indole-9,10(1H)-dicarboxylate | C48H59N3O10SSi | 详情 | 详情 |