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【结 构 式】 
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【分子编号】17679 【品名】(3S,3aR,6aR)-2-oxo-3,3a,4,6a-tetrahydro-2H-cyclopenta[b]furan-3-yl acetate 【CA登记号】 |
【 分 子 式 】C9H10O4 【 分 子 量 】182.176 【元素组成】C 59.34% H 5.53% O 35.13% |
合成路线1
该中间体在本合成路线中的序号：(IV)The cyclization of glyoxylic acid (I) with cyclopentadiene (II) gives the racemic hydroxylactone (III), which is acylated with Ac2O to yield acetoxy compound (rac)-(IV). The enzymatic optical resolution of (rac)-(IV) by means of Pseudomonas fluorescens affords the chiral hydroxylactone (-)-(V), which is reduced with LiAlH4 in refluxing THF to provide the lactol (VI). The oxidation of (VI) with NaIO4 in ethyl ether/water gives the chiral carbaldehyde (VII), which is reduced with NaBH4 in ethanol to afford the diol (VIII). The reaction of (VIII) with triphosgene by means of TEA in dichloromethane affords the cyclic carbonate (IX), which is condensed with chloropurine (X) by means of Pd(PPh3)4 in DMSO/THF to provide the adduct (XI). Finally, this compound is hydrolyzed with NaOH to afford the target (-)-carbovir.
| 【1】 Yu, J.; Olivo, H.F.; Practical enantiodivergent syntheses of both enantiomers of carbovir, 1592U89 and six-membered ring analogues. J Chem Soc - Perkins Trans I 1998, 3, 3, 391-2. |
| 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) | 15618 | 2-Oxoacetic acid; Glyoxylic Acid | 298-12-4 | C2H2O3 | 详情 | 详情 |
| (II) | 11183 | 1,3-Cyclopentadiene | C5H6 | 详情 | 详情 | |
| (III) | 55545 | (3S,3aR,6aR)-3-hydroxy-3,3a,4,6a-tetrahydro-2H-cyclopenta[b]furan-2-one | C7H8O3 | 详情 | 详情 | |
| (IV) | 17679 | (3S,3aR,6aR)-2-oxo-3,3a,4,6a-tetrahydro-2H-cyclopenta[b]furan-3-yl acetate | C9H10O4 | 详情 | 详情 | |
| (V) | 17678 | (3S,3aR,6aR)-3-hydroxy-3,3a,4,6a-tetrahydro-2H-cyclopenta[b]furan-2-one | C7H8O3 | 详情 | 详情 | |
| (VI) | 55544 | (3S,3aR,6aR)-3,3a,4,6a-tetrahydro-2H-cyclopenta[b]furan-2,3-diol | C7H10O3 | 详情 | 详情 | |
| (VII) | 17682 | (1S,2R)-2-hydroxy-3-cyclopentene-1-carbaldehyde | C6H8O2 | 详情 | 详情 | |
| (VIII) | 17671 | (1R,5R)-5-(hydroxymethyl)-2-cyclopenten-1-ol | C6H10O2 | 详情 | 详情 | |
| (IX) | 17673 | (4aR,7aR)-4,4a,5,7a-tetrahydrocyclopenta[d][1,3]dioxin-2-one | C7H8O3 | 详情 | 详情 | |
| (X) | 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 |
| (XI) | 17650 | [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol | C11H12ClN5O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXXVIII)5) The water promoted condensation of glyoxylic acid (XXXV) with cyclopentadiene (XXXVI) gives the racemic cis-hydroxylactone (XXXVII), which is acetylated with acetic anhydride to the acetate (XXXVIII). The selective enzymatic hydrolysis of (XXXVIII) with Pseudomonas fluorescens lipase yields the pre (-)-enantiomer (XXXIX), which is reduced with LiAlH4 in refluxing THF, affording triol (XL). The oxidation of the vicinal glycol of (XL) with NaIO4 in ethyl ether/water yields the hydroxyaldehyde (XLI), which is reduced with NaBH4 in ethanol to give the key intermediate 5(R)-(hydroxymethyl)-2-cyclopenten-1(R)-ol (XXX). This compound, by reaction with triphosgene and triethylamine in dichloromethane, results in the cyclic carbonate intermediate (XXXII), already reported.
| 【1】 Yu, J.; Olivo, H.F.; Practical enantiodivergent syntheses of both enantiomers of carbovir, 1592U89 and six-membered ring analogues. J Chem Soc - Perkins Trans I 1998, 3, 3, 391-2. |
| 【2】 Graul, A.; Castaner, J.; Leeson, P.A.; Abacavir Sulfate. Drugs Fut 1998, 23, 11, 1155-1167. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXX) | 17671 | (1R,5R)-5-(hydroxymethyl)-2-cyclopenten-1-ol | C6H10O2 | 详情 | 详情 | |
| (XXXII) | 17673 | (4aR,7aR)-4,4a,5,7a-tetrahydrocyclopenta[d][1,3]dioxin-2-one | C7H8O3 | 详情 | 详情 | |
| (XXXV) | 15618 | 2-Oxoacetic acid; Glyoxylic Acid | 298-12-4 | C2H2O3 | 详情 | 详情 |
| (XXXVI) | 11183 | 1,3-Cyclopentadiene | C5H6 | 详情 | 详情 | |
| (XXXVII) | 63844 | (rac)-(3R*,3aS*,6aS*)-3-hydroxy-3,3a,4,6a-tetrahydro-2H-cyclopenta[b]furan-2-one | C7H8O3 | 详情 | 详情 | |
| (XXXVIII) | 17679 | (3S,3aR,6aR)-2-oxo-3,3a,4,6a-tetrahydro-2H-cyclopenta[b]furan-3-yl acetate | C9H10O4 | 详情 | 详情 | |
| (XXXIX) | 17678 | (3S,3aR,6aR)-3-hydroxy-3,3a,4,6a-tetrahydro-2H-cyclopenta[b]furan-2-one | C7H8O3 | 详情 | 详情 | |
| (XL) | 17681 | (1S)-1-[(1S,2R)-2-hydroxy-3-cyclopenten-1-yl]-1,2-ethanediol | C7H12O3 | 详情 | 详情 | |
| (XLI) | 17682 | (1S,2R)-2-hydroxy-3-cyclopentene-1-carbaldehyde | C6H8O2 | 详情 | 详情 |