|
【结 构 式】 
|
【分子编号】33174 【品名】(1S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-ol 【CA登记号】 |
【 分 子 式 】C11H22O2Si 【 分 子 量 】214.37998 【元素组成】C 61.63% H 10.34% O 14.93% Si 13.1% |
合成路线1
该中间体在本合成路线中的序号：(VIII)The photooxidation of cyclopentadiene (I) gives cis-4-cyclopentene-1,3-diol (II), which is acylated with Ac2O to yield the diacetate (II). Enzymatic selective hydrolysis of (II) using porcine pancreas lipase (PPL) affords the chiral monoacetate (IV), which is protected with dihydropyran (DHP) and Ts-OH to provide the tetrahydropyranyl ether (V). The hydrolysis of the acetate group of (V) with KOH in methanol gives the alcohol (VI), which is silylated with TbdmsCl and imidazole to yield the silyl ether (VII). Elimination of the THP-protecting group of (VII) with Me2AlCl in dichloromethane affords the cyclopentenol (VIII), which is oxidized with PCC to the cyclopentenone (IX). The condensation of (IX) with chloroiodomethane and BuLi in THF gives the chiral chloromethyl derivative (X), which is treated with potassium methoxide in THF to obtain the chiral epoxide (XI). Stereocontrolled opening of the epoxide ring of (XI) by means of DIBAL in hexane provides the cyclopentenyl-methanol derivative (XII), which is desilylated with TBAF in THF to give the chiral diol (XIII). The esterification of the diol (XIII) with methyl chloroformate and pyridine yields the bis-carbonate (XIV), which is condensed with 2-amino-6-chloropurine (XV) by means of Pd(PPh3)4 in DMF to afford the carbocyclic purine derivative (XVI). Finally, this compound is hydrolyzed with NaOH in refluxing water to provide the target carbocyclic guanine.
| 【1】 Nokami, J.; et al.; Palladium-catalyzed chemoselective reaction of allylic carbonate with nucleoside bases and its application for the synthesis of carbocyclic nucleosides. (-)-and (+)-carbovirs. Chem Lett 1994, 1071. |
| 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) | 11183 | 1,3-Cyclopentadiene | C5H6 | 详情 | 详情 | |
| (II) | 33168 | (1R,3S)-4-cyclopentene-1,3-diol | C5H8O2 | 详情 | 详情 | |
| (III) | 45374 | (1R,4S)-4-(acetoxy)-2-cyclopenten-1-yl acetate | C9H12O4 | 详情 | 详情 | |
| (IV) | 45407 | (1R,4S)-4-hydroxy-2-cyclopenten-1-yl acetate; (1S,4R)-4-acetoxy-2-cyclopentenol | 60410-16-4 | C7H10O3 | 详情 | 详情 |
| (V) | 45339 | C8H11N | 详情 | 详情 | ||
| (VI) | 45400 | (1R,4S)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-cyclopenten-1-ol | C11H18O3 | 详情 | 详情 | |
| (VII) | 45401 | tert-butyl(dimethyl)([(1R,4S)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-cyclopenten-1-yl]oxy)silane; tert-butyl(dimethyl)silyl (1R,4S)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-cyclopenten-1-yl ether | C17H32O3Si | 详情 | 详情 | |
| (VIII) | 33174 | (1S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-ol | C11H22O2Si | 详情 | 详情 | |
| (IX) | 13805 | (4R)-4-[[tert-Butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-one | C11H20O2Si | 详情 | 详情 | |
| (X) | 45402 | (1S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-(chloromethyl)-2-cyclopenten-1-ol | C12H23ClO2Si | 详情 | 详情 | |
| (XI) | 45403 | tert-butyl(dimethyl)silyl (3S,5R)-1-oxaspiro[2.4]hept-6-en-5-yl ether; tert-butyl(dimethyl)[(3S,5R)-1-oxaspiro[2.4]hept-6-en-5-yloxy]silane | C12H22O2Si | 详情 | 详情 | |
| (XII) | 45404 | ((1S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-yl)methanol | C12H24O2Si | 详情 | 详情 | |
| (XIII) | 45405 | (1R,4S)-4-(hydroxymethyl)-2-cyclopenten-1-ol | C6H10O2 | 详情 | 详情 | |
| (XIV) | 45406 | [(1S,4R)-4-[(methoxycarbonyl)oxy]-2-cyclopenten-1-yl]methyl methyl carbonate | C10H14O6 | 详情 | 详情 | |
| (XV) | 11644 | 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine | 10310-21-1 | C5H4ClN5 | 详情 | 详情 |
| (XVI) | 45398 | [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methyl methyl carbonate | C13H14ClN5O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(rac)(XIV)The rearrangement of furfuryl alcohol (XI) in acidic medium (KH2PO4, H3PO4) gives 4-hydoxy-2-penten-1-one (XII), which is silylated with TBDMS-Cl, Et3N and DMAP in THF yielding the silyl ether (XIII). The reduction of (XIII) with LiAlH4 in toluene affords the (rac)(cis)-4-(tert-butyldimethylsilyloxy)-2-penten-1-ol (XIV), which is submitted to optical resolution by digestion with pancreatin (8xUSP) and vinyl acetate in tert-butyl methyl ether yielding a mixture of (1S,4R)-4-(tert-butyldimethylsilyloxy)-2-cyclopentenyl acetate (XV) and (1R,4S)- 4-(tert-butyldimethylsilyloxy)-2-cyclopenten-1-ol (XVI), which were separated by column chromatography. Both compounds (XV) and (XVI) were used by independent routes to obtain the target compound: a) The desilylation of (XV) with TBAF in THF gives the previously described (1R,4S)-4-acetoxy-2-cyclopenten-1-ol (VI), which is converted into the target compound by the previously described route (VI) - (VII) - (VIII) - (X) - target adenine derivative. b) The hydrogenation of (1R,4S)- 4-(tert-butyldimethylsilyloxy)-2-cyclopenten-1-ol (XVI) with H2 over Ni2B in ethanol gives the corresponding saturated alcohol (XVII), which is treated with methanesulfonyl chloride and triethylamine in tert-butyl methyl ether yielding the mesylate (XVIII). The condensation of (XVIII) with adenine (IX) by means of NaH in hot DMA affords the silylated target compound (XIX), which is finally deprotected with HCl in ethanol.
| 【1】 Borcherding, D.R.; et al.; Carbocyclic nucleosides as inhibitors of human Tumor Necrosis Factor-alpha production: Effects of the stereoisomers of (3-hydroxycyclopentyl)adenines. J Med Chem 1996, 39, 13, 2615. |
| 【2】 Watson, T.J.N.; et al.; Development of the carbocyclic nucleoside MDL 201449A. A tumor necrosis factor-alpha inhibitor. Org Process Res Dev 1998, 2, 6, 357. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (rac)(XIV) | 33174 | (1S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-ol | C11H22O2Si | 详情 | 详情 | |
| (V) | 24543 | vinyl acetate | 108-05-4 | C4H6O2 | 详情 | 详情 |
| (VI) | 33169 | (1S,4R)-4-hydroxy-2-cyclopenten-1-yl acetate | C7H10O3 | 详情 | 详情 | |
| (VII) | 33170 | (1R,3S)-3-hydroxycyclopentyl acetate | C7H12O3 | 详情 | 详情 | |
| (VIII) | 33171 | (1R,3S)-3-[(methylsulfonyl)oxy]cyclopentyl acetate | C8H14O5S | 详情 | 详情 | |
| (IX) | 10343 | 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine | 73-24-5 | C5H5N5 | 详情 | 详情 |
| (X) | 33172 | (1R,3R)-3-(6-amino-9H-purin-9-yl)cyclopentyl acetate | C12H15N5O2 | 详情 | 详情 | |
| (XI) | 13848 | 2-Furylmethanol; Furfuryl Alcohol | 98-00-0 | C5H6O2 | 详情 | 详情 |
| (XII) | 33173 | 4-hydroxy-2-cyclopenten-1-one | C5H6O2 | 详情 | 详情 | |
| (XIII) | 13805 | (4R)-4-[[tert-Butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-one | C11H20O2Si | 详情 | 详情 | |
| (XV) | 33175 | (1S)-2-cyclopenten-1-yl acetate | C7H10O2 | 详情 | 详情 | |
| (XVI) | 64705 | (1R,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclopenten-1-ol | C11H22O2Si | 详情 | 详情 | |
| (XVII) | 33176 | (1S,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]cyclopentanol | C11H24O2Si | 详情 | 详情 | |
| (XVIII) | 33177 | (1R,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-yl methanesulfonate | C12H24O4SSi | 详情 | 详情 | |
| (XIX) | 33178 | 9-((1R,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]cyclopentyl)-9H-purin-6-amine; 9-((1R,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]cyclopentyl)-9H-purin-6-ylamine | C16H27N5OSi | 详情 | 详情 |