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【结 构 式】 
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【分子编号】15026 【品名】(2R)-3-[[tert-butyl(diphenyl)silyl]oxy]-2-methoxypropanal 【CA登记号】 |
【 分 子 式 】C20H26O3Si 【 分 子 量 】342.51014 【元素组成】C 70.14% H 7.65% O 14.01% Si 8.2% |
合成路线1
该中间体在本合成路线中的序号：(XXXVIII)Aldehyde (XXI): The condensation of oxazolidinone (XXXVII) with aldehyde (XXXVIII) by means of dibutylboron trifluoromethanesulfonate in dichloromethane gives compound (XXXIX), which is reduced with LiBH4, tosyl chloride and lithium triethylborohydride as before, yielding the alcohol (XL). The deprotection of (XL) with tetrabutylammonium fluoride in THF followed by formation of a dioxane ring with p-methoxybenzaldehyde diethyl acetal and CSA in dichloromethane affords compound (XLI), which is submitted to a reductive ring opening with diiosbutylaluminum hydride in dichloromethane, followed by an oxidation with oxalyl chloride in DMSO/dichloromethane, yielding the aldehyde (XLII). The condensation of (XLII) with the unsaturated iodo compound (XLIII) by means of CrCl2 in DMSO gives the hydroxy derivative (XLIV), which is finally silylated with triisopropylsilyl trifluoromethanesulfonate in dichloromethane, selectively desilylated with HF - pyridine and oxidized with oxalyl chloride in DMSO/dichloromethane to the intermediate aldehyde (XXI) (see K.C. Nicolau et al., J Chem Soc Chem Commun 1993, 7: 619). The intermediate (XLIII) is prepared by ozonolysis of the protected unsaturated diol (XLV), followed by reaction with dimethylsulfide and tetrabromomethane - triphenylphosphine to obtain an acetylenic intermediate, which is methylated with butyllithium and methyl iodide to the acetylene (XLVI). Finally, this compound is iodinated with iodine and (cyclopentadienyl)2ZrHCl in dichloromethane to the intermediate (XLIII) (see K.C. Nicolau et al., J Chem Soc Chem Commun 1993, 7: 619). (1,2)
| 【1】 Nicolaou, K.C.; Piscopio, A.D.; Bertinato, P.; Chakraborty, T.K.; Minowa, N.; Koide, K.; Total Synthesis of Rapamycin. Chemistry (Weinheim) 1995, 1, 5, 318. |
| 【2】 Nicolaou, K.C.; Chakraborty, T.K.; Piscopio, A.D.; Minowa, N.; Bertinato, P.; Total synthesis of rapamycin. J Am Chem Soc 1993, 115, 10, 4419. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXI) | 15009 | (3S,4R,5E,7R,8S,9R,10R,12S)-8-methoxy-3,9-bis[(4-methoxybenzyl)oxy]-4,6,10,12-tetramethyl-7-[(triisopropylsilyl)oxy]-5,13-tetradecadienal | C44H70O7Si | 详情 | 详情 | |
| (XXXVII) | 15025 | (4R,5S)-4-methyl-3-[(4S)-4-methyl-5-hexenoyl]-5-phenyl-1,3-oxazolan-2-one | C17H21NO3 | 详情 | 详情 | |
| (XXXVIII) | 15026 | (2R)-3-[[tert-butyl(diphenyl)silyl]oxy]-2-methoxypropanal | C20H26O3Si | 详情 | 详情 | |
| (XXXIX) | 15027 | (4R,5S)-3-[(2R,4S)-2-((1R,2R)-3-[[tert-butyl(diphenyl)silyl]oxy]-1-hydroxy-2-methoxypropyl)-4-methyl-5-hexenoyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one | C37H47NO6Si | 详情 | 详情 | |
| (XL) | 15028 | (2R,3R,4R,6S)-1-[[tert-butyl(diphenyl)silyl]oxy]-2-methoxy-4,6-dimethyl-7-octen-3-ol | C27H40O3Si | 详情 | 详情 | |
| (XLI) | 15029 | 4-[(4R,5R)-4-[(1R,3S)-1,3-dimethyl-4-pentenyl]-5-methoxy-1,3-dioxan-2-yl]phenyl methyl ether; (4R,5R)-4-[(1R,3S)-1,3-dimethyl-4-pentenyl]-5-methoxy-2-(4-methoxyphenyl)-1,3-dioxane | C19H28O4 | 详情 | 详情 | |
| (XLII) | 15030 | (2S,3R,4R,6S)-2-methoxy-3-(4-methoxybenzyl)-4,6-dimethyl-7-octenal | C19H28O3 | 详情 | 详情 | |
| (XLIII) | 15031 | tert-butyl(dimethyl)silyl (3S,4S,5E)-6-iodo-3-(4-methoxybenzyl)-4-methyl-5-heptenyl ether; tert-butyl[[(3S,4S,5E)-6-iodo-3-(4-methoxybenzyl)-4-methyl-5-heptenyl]oxy]dimethylsilane | C22H37IO2Si | 详情 | 详情 | |
| (XLIV) | 15032 | (3S,4S,5E,7R,8S,9R,10R,12S)-1-[[tert-butyl(dimethyl)silyl]oxy]-8-methoxy-3,9-bis(4-methoxybenzyl)-4,6,10,12-tetramethyl-5,13-tetradecadien-7-ol | C41H66O5Si | 详情 | 详情 | |
| (XLV) | 15033 | tert-butyl[[(3S,4R)-3-(4-methoxybenzyl)-4-methyl-5-hexenyl]oxy]dimethylsilane; tert-butyl(dimethyl)silyl (3S,4R)-3-(4-methoxybenzyl)-4-methyl-5-hexenyl ether | C21H36O2Si | 详情 | 详情 | |
| (XLVI) | 15034 | tert-butyl(dimethyl)silyl (3S,4S)-3-(4-methoxybenzyl)-4-methyl-5-heptynyl ether; tert-butyl[[(3S,4S)-3-(4-methoxybenzyl)-4-methyl-5-heptynyl]oxy]dimethylsilane | C22H36O2Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXXI)Synthesis of dysinosin A: The reaction of the commercially available D-mannitol derivative (XXVII) with NaH and MeI in DMF gives the dimethoxy compound (XXVIII), which is hydrogenated with H2 over Pd/C in EtOH/EtOAc to yield the dimethoxy-D-mannitol (XXIX). The selective silylation of the primary OH groups of (XXIX) with Tbdps-Cl and imidazole affords the bis silyl ether (XXX), which is submitted to an oxidative cleavage of its vicinal diol group by means of Pb(OAc)4 to provide 2(R)-methoxy-3-(Tbdps-O)propanal (XXXI) (3). The oxidation of (XXXI) with NaClO2 gives the corresponding carboxylic acid (XXXII), which is condensed with D-leucine benzyl ester (XXXIII) by means of EDC and HOBt in dichloromethane to yield adduct (XXXIV). The reductive cleavage of the benzyl group of (XXXIV) with H2 over Pd/C in methanol affords the substituted leucine (XXXV), which is condensed with the perhydroindole intermediate (XIII) by means of Bop-Cl and DIEA in acetonitrile to provide the amide (XXXVI). The hydrolysis of the methyl ester group of (XXXVI) with LiOH in THF/MeOH gives the carboxylic acid (XXXVII), which is condensed with the aminoethyl-3-pyrroline intermediate (XXVI) by means of EDC and HOBt in dichloromethane to yield the amide intermediate (XXXVIII). The cleavage of the silyl ether group of (XXXVIII) by means of TBAF in THF affords the primary alcohol (XXXIX), which is treated with Pyr/SO3 and Bu2SnO to provide the sulfate ester (XL). Finally, this compound is fully deprotected by means of TFA in dichloromethane and purified by means of preparative HPLC to obtain the target dysinosin A (2).
| 【1】 Nicolaou, K.C.; Piscopio, A.D.; Bertinato, P.; Chakraborty, T.K.; Minowa, N.; Koide, K.; Total Synthesis of Rapamycin. Chemistry (Weinheim) 1995, 1, 5, 318. |
| 【2】 Hanessian, S.; Margarita, R.; Hall, A.; Johnstone, S.; Tremblay, M.; Parlanti, L.; Total synthesis and structural confirmation of the marine natural product Dysinosin A: A novel inhibitor of thrombin and Factor VIIa. J Am Chem Soc 2002, 124, 45, 13342. |
| 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) | 64913 | methyl 5,6-bis{[(methyloxy)methyl]oxy}octahydro-1H-indole-2-carboxylate | C14H25NO6 | 详情 | 详情 | |
| (XXVI) | 64925 | C17H30N4O4 | 详情 | 详情 | ||
| (XXVII) | 64926 | C20H22O6 | 详情 | 详情 | ||
| (XXVIII) | 64927 | C22H26O6 | 详情 | 详情 | ||
| (XXIX) | 64928 | 2,5-bis(methyloxy)-1,3,4,6-hexanetetrol | C8H18O6 | 详情 | 详情 | |
| (XXX) | 64929 | 2,2,13,13-tetramethyl-6,9-bis(methyloxy)-3,3,12,12-tetraphenyl-4,11-dioxa-3,12-disilatetradecane-7,8-diol | C40H54O6Si2 | 详情 | 详情 | |
| (XXXI) | 15026 | (2R)-3-[[tert-butyl(diphenyl)silyl]oxy]-2-methoxypropanal | C20H26O3Si | 详情 | 详情 | |
| (XXXII) | 64930 | 3-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-2-(methyloxy)propanoic acid | C20H26O4Si | 详情 | 详情 | |
| (XXXIII) | 28648 | benzyl (2R)-2-amino-4-methylpentanoate | C13H19NO2 | 详情 | 详情 | |
| (XXXIV) | 64931 | phenylmethyl 2-{[3-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-2-(methyloxy)propanoyl]amino}-4-methylpentanoate | C33H43NO5Si | 详情 | 详情 | |
| (XXXV) | 64932 | N-[3-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-2-(methyloxy)propanoyl]leucine | C26H37NO5Si | 详情 | 详情 | |
| (XXXVI) | 64933 | methyl 1-(2-{[2-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-2-(methyloxy)acetyl]amino}-4-methylpentanoyl)-5,6-bis{[(methyloxy)methyl]oxy}octahydro-1H-indole-2-carboxylate | C39H58N2O10Si | 详情 | 详情 | |
| (XXXVII) | 64934 | 1-(2-{[2-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-2-(methyloxy)acetyl]amino}-4-methylpentanoyl)-5,6-bis{[(methyloxy)methyl]oxy}octahydro-1H-indole-2-carboxylic acid | C38H56N2O10Si | 详情 | 详情 | |
| (XXXVIII) | 64935 | C55H84N6O13Si | 详情 | 详情 | ||
| (XXXIX) | 64936 | C39H66N6O13 | 详情 | 详情 | ||
| (XL) | 64937 | 2-{[(2-{1-[({[(1,1-dimethylethyl)oxy]carbonyl}amino)({[(1,1-dimethylethyl)oxy]carbonyl}imino)methyl]-2,5-dihydro-1H-pyrrol-3-yl}ethyl)amino]carbonyl}-1-(4-methyl-2-{[2-(methyloxy)-2-(sulfonatooxy)acetyl]amino}pentanoyl)-5,6-bis{[(methyloxy)methyl]ox | C39H65N6O16S | 详情 | 详情 |