|
【结 构 式】 
|
【分子编号】25839 【品名】(1S,2S,3S,4S,5S)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol 【CA登记号】 |
【 分 子 式 】C6H10O5 【 分 子 量 】162.1424 【元素组成】C 44.45% H 6.22% O 49.34% |
合成路线1
该中间体在本合成路线中的序号：(IX)In a related procedure, 1,6-anhydro-L-gulose (IX) was obtained from L-gulose (VIII) by treatment with 0.5 N HCl. Oxidative cleavage of (IX) by NaIO4, followed by reduction of the aldehyde groups with NaBH4, led to the dioxolane triol (X), which was further protected as the isopropylidene ketal (XI). Benzoylation of the free hydroxyl of (XI), followed by acidic hydrolysis of the acetonide group, furnished the benzoate diol (XII). Then, oxidation of the vicinal diol moiety of (XII), by means of RuO2 in the presence of NaIO4, afforded carboxylic acid (III). Oxidative decarboxylation of acid (III) with lead tetraacetate produced the key acetoxy dioxolane (XIII). This was coupled with the silylated N-acetylcytosine (XIV) in the presence of trimethylsilyl triflate to yield a mixture of anomers, which were separated by column chromatography. Final hydrolysis of the desired isomer (VII) was then performed by treatment with methanolic ammonia.
| 【1】 Kim, H.O.; et al.; Potent anti-HIV and anti-HBV activities of (-)-L-beta-dioxolane-C and (+)-L-beta-dioxolane-T and their asymmetric syntheses. Tetrahedron Lett 1992, 33, 46, 6899. |
| 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) | 25844 | (2S,4S)-2-[(benzoyloxy)methyl]-1,3-dioxolane-4-carboxylic acid | C12H12O6 | 详情 | 详情 | |
| (VII) | 56696 | {(2S,4S)-4-[4-(acetylamino)-2-oxo-1(2H)-pyrimidinyl]-1,3-dioxolan-2-yl}methyl benzoate | C17H17N3O6 | 详情 | 详情 | |
| (VIII) | 36947 | (3S,4S,5S,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetrol | C6H12O6 | 详情 | 详情 | |
| (IX) | 25839 | (1S,2S,3S,4S,5S)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol | C6H10O5 | 详情 | 详情 | |
| (X) | 56697 | (1R)-1-[(2S,4S)-2-(hydroxymethyl)-1,3-dioxolan-4-yl]-1,2-ethanediol | C6H12O5 | 详情 | 详情 | |
| (XI) | 56698 | C9H16O5 | 详情 | 详情 | ||
| (XII) | 56699 | {(2S,4S)-4-[(1R)-1,2-dihydroxyethyl]-1,3-dioxolan-2-yl}methyl benzoate | C13H16O6 | 详情 | 详情 | |
| (XIII) | 25845 | [(2S)-4-(acetoxy)-1,3-dioxolan-2-yl]methyl benzoate | C13H14O6 | 详情 | 详情 | |
| (XIV) | 56700 | N-{2-[(trimethylsilyl)oxy]-4-pyrimidinyl}acetamide | C9H15N3O2Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The reaction of 1,6-anhydro-beta-D-glucopyranose (I) with tosyl chloride in pyridine gives 1,6-anhydro-2,4-di-O-(p-toluenesulfonyl)-beta-D-glucopyranose (II), which is oxidized with NaBrO3 and RuCl3 in acetonitrile/water yielding 1,6-anhydro-2,4-di-O-(p-toluenesulfonyl)-beta-D-glucopyranos-3-ulose (III). Finally, the deoxygenation of the ditosylate (III) to the desired intermediate (IV) is performed with Zn dust and NH4OAc in THF. The 1,6-anhydro-2,4-di-O-(p-toluenesulfonyl)-beta-D-glucopyranose (II) obtained before can be reduced with Super-hydride in THF yielding the bicyclooctanol (V), which is finally oxidized to the target ketone (IV) by means of pyridinium chlorochromate (PCC) in dichloromethane. The treatment of D-glucose (VI) successively with TsCl and pyridine, with DBU and finally again with TsCl gives the previously reported 1,6-anhydro-2,4-di-O-(p-toluenesulfonyl)-beta-D-glucopyranose (II), which is reduced to the previously reported bicyclooctanol (V) with LiEt3BH. Finally, this compound is oxidized with PCC as before to the target ketone (IV).
| 【1】 Delorme, D.; et al.; Dioxabicyclooctanyl naphthalenenitriles as nonredox 5-lipoxygenase inhibitors: Structure-activity relationship study directed toward the improvement of metabolic stability. J Med Chem 1996, 39, 20, 3951. |
| 【2】 Girard, Y.; Dube, D.; Fortin, R.; Hamel, P.; Delorme, D.; Lepine, C. (Merck Frosst Canada Inc.); Heteroarylnaphthalenes as inhibitors of leukotriene biosynthesis. EP 0579304; JP 1994087847; US 5308852; WO 9400444 . |
| 【3】 Belyk, K.M.; et al.; Practical synthesis of 1,6-anhydro-2,4-dideoxy-beta-D-glycero-hexapyramos-3-ulose from levoglucosan. J Org Chem 2000, 65, 8, 2588. |
| 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) | 25839 | (1S,2S,3S,4S,5S)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol | C6H10O5 | 详情 | 详情 | |
| (II) | 38605 | (2S,3S,4S)-3-hydroxy-2-[[(4-methylphenyl)sulfonyl]oxy]-6,8-dioxabicyclo[3.2.1]oct-4-yl 4-methylbenzenesulfonate | C20H22O9S2 | 详情 | 详情 | |
| (III) | 38606 | (2R,4R)-4-[[(4-methylphenyl)sulfonyl]oxy]-3-oxo-6,8-dioxabicyclo[3.2.1]oct-2-yl 4-methylbenzenesulfonate | C20H20O9S2 | 详情 | 详情 | |
| (IV) | 38608 | 6,8-dioxabicyclo[3.2.1]octan-3-one | C6H8O3 | 详情 | 详情 | |
| (V) | 38607 | (3S)-6,8-dioxabicyclo[3.2.1]octan-3-ol | C6H10O3 | 详情 | 详情 | |
| (VI) | 38609 | (2S,3S,4S)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol | C6H10O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)L-Gulono-gamma-lactone (I) was reduced with DIBAL and then protected as the diisopropylidene ketal (III). This was converted to 1,6-anhydrogulopyranose (IV) upon treatment with 0.5N HCl. Subsequent oxidative cleavage of (IV) with NaIO4, followed by reduction with NaBH4 provided triol (V), which was protected as the isopropylidene derivative (VI) with acetone and TsOH. Condensation of (VI) with benzoyl chloride in the presence of pyridine yielded benzoate ester (VII). Then, ketal deprotection of (VII) afforded diol (VIII). Oxidative treatment with NaIO4/RuO2 produced acid (IX), and further oxidative decarboxylation with Pb(OAc)4 furnished dioxolanyl acetate (X). 5-Iodouracil (XI) was silylated using hexamethyldisilazane and a catalytic amount of (NH4)2SO4. The resulting silylated uracil (XII) was coupled with dioxolanyl acetate (X) in the presence of trimethylsilyl triflate to afford an anomeric mixture of nucleosides (XIII). Title compound was then obtained by deprotection of the benzoate ester of the mixture (XIII) with methanolic ammonia, followed by chromatographic isolation of the desired L-anomer.
| 【1】 Kim, H.O.; et al.; L-beta-(2S,4S)- and L-alpha-(2S,4R)-dioxolanyl nucleosides as potential anti-HIV agents: Asymetric synthesis and structure - Activity relationships. J Med Chem 1993, 36, 5, 519. |
| 【2】 Lin, J.-S.; et al.; Structure-activity relationships of L-dioxolane uracil nucleosides as anti-epstein barr virus agents. J Med Chem 1999, 42, 12, 2212. |
| 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) | 25836 | (3S,4R)-5-[(1S)-1,2-dihydroxyethyl]-3,4-dihydroxydihydro-2(3H)-furanone | C6H10O6 | 详情 | 详情 | |
| (II) | 25837 | (3S,4R)-5-[(1S)-1,2-dihydroxyethyl]tetrahydro-2,3,4-furantriol | C6H12O6 | 详情 | 详情 | |
| (III) | 25838 | (3aS,6aS)-6-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-ol | 14131-84-1 | C12H20O6 | 详情 | 详情 |
| (IV) | 25839 | (1S,2S,3S,4S,5S)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol | C6H10O5 | 详情 | 详情 | |
| (V) | 25840 | (1S)-1-[(2S)-2-(hydroxymethyl)-1,3-dioxolan-4-yl]-1,2-ethanediol | C6H12O5 | 详情 | 详情 | |
| (VI) | 25841 | 4-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-1,3-dioxqlan-2(S)-ymethanol | C9H16O5 | 详情 | 详情 | |
| (VII) | 25842 | Benzoic acid 4-(2,2-dimethyl-1,3-dioxolan-4(S)-yl)-1,3-dioxolan-2(S)-ylmethyl ester | C16H20O6 | 详情 | 详情 | |
| (VIII) | 25843 | [(2S)-4-[(1S)-1,2-dihydroxyethyl]-1,3-dioxolan-2-yl]methyl benzoate | C13H16O6 | 详情 | 详情 | |
| (IX) | 25844 | (2S,4S)-2-[(benzoyloxy)methyl]-1,3-dioxolane-4-carboxylic acid | C12H12O6 | 详情 | 详情 | |
| (X) | 25845 | [(2S)-4-(acetoxy)-1,3-dioxolan-2-yl]methyl benzoate | C13H14O6 | 详情 | 详情 | |
| (XI) | 11876 | 1-[(2R,4S,5R)-4-Hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5,6-diiododihydro-2,4(1H,3H)-pyrimidinedione | C9H12I2N2O5 | 详情 | 详情 | |
| (XII) | 25846 | 5-iodo-2,4-bis[(trimethylsilyl)methyl]pyrimidine | C12H23IN2Si2 | 详情 | 详情 | |
| (XIII) | 25847 | [(2S)-4-[5-iodo-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-1,3-dioxolan-2-yl]methyl benzoate | C15H13IN2O6 | 详情 | 详情 |