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【结 构 式】 
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【分子编号】17672 【品名】[(1R,2R)-2-[(methoxycarbonyl)oxy]-3-cyclopenten-1-yl]methyl methyl carbonate 【CA登记号】 |
【 分 子 式 】C10H14O6 【 分 子 量 】230.21756 【元素组成】C 52.17% H 6.13% O 41.7% |
合成路线1
该中间体在本合成路线中的序号：(VIII)The condensation of the cis-dibenzoyloxycyclopentene (I) with the lithium salt of 2-nitrovinyl(phenyl)sulfone (II) by means of a chiral palladium catalyst and PPh3 in THF gives the chiral isoxazoline-N oxide (III), which is deoxygenated by means of SnCl2 in acetonitrile, yielding the isoxazoline (IV). The solvolysis of (IV) with K2CO3 in methanol affords the methoxy compound (V), which is treated with Mo(CO)6 and boric acid in methanol to provide the chiral 2-hydroxy-3-cyclopentene-1-carboxylic acid methyl ester (VI). The reduction of (VI) with LiAlH4 in ether yields the hydroxymethyl derivative (VII), which is esterified with methyl chloroformate and BuLi in THF to afford the bis-carbonate (VIII). The condensation of (VIII) with 2-amino-6-chloropurine (IX) by means of a Pd catalyst in THF provides the carbocyclic purine (X), which is finally treated with NaOH in refluxing water to yield the target carbocyclic guanine.
| 【1】 Trost, B.M.; et al.; A novel Pd-catalyzed cycloalkylation to isoxazoline 2-oxides. Application for the asymmetric synthesis of carbanucleosides. J Am Chem Soc 1992, 114, 22, 8745. |
| 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) | 37776 | (1R,4S)-4-(benzoyloxy)-2-cyclopenten-1-yl benzoate | C19H16O4 | 详情 | 详情 | |
| (II) | 45393 | lithium oxo[(phenylsulfonyl)methylene]-lambda(5)-azanolate | C7H6LiNO4S | 详情 | 详情 | |
| (III) | 45394 | (3aS,6aR)-3-(phenylsulfonyl)-4,6a-dihydro-3aH-cyclopenta[d]isoxazol-2-ium-2-olate | C12H11NO4S | 详情 | 详情 | |
| (IV) | 45395 | (3aS,6aR)-3-(phenylsulfonyl)-4,6a-dihydro-3aH-cyclopenta[d]isoxazole; (3aS,6aR)-4,6a-dihydro-3aH-cyclopenta[d]isoxazol-3-yl phenyl sulfone | C12H11NO3S | 详情 | 详情 | |
| (V) | 45396 | (3aS,6aR)-3-methoxy-4,6a-dihydro-3aH-cyclopenta[d]isoxazole; (3aS,6aR)-4,6a-dihydro-3aH-cyclopenta[d]isoxazol-3-yl methyl ether | C7H9NO2 | 详情 | 详情 | |
| (VI) | 45397 | methyl (1S,2R)-2-hydroxy-3-cyclopentene-1-carboxylate | C7H10O3 | 详情 | 详情 | |
| (VII) | 17671 | (1R,5R)-5-(hydroxymethyl)-2-cyclopenten-1-ol | C6H10O2 | 详情 | 详情 | |
| (VIII) | 17672 | [(1R,2R)-2-[(methoxycarbonyl)oxy]-3-cyclopenten-1-yl]methyl methyl carbonate | C10H14O6 | 详情 | 详情 | |
| (IX) | 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 |
| (X) | 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：(X)The condensation of the chiral oxazolidinone (I) with the pentenoic anhydride (II) by means of n-BuLi in THF gives the N-pentenoyloxazolidinone (III), which is condensed with acrolein (IV) catalyzed by TiCl4 and (-)-spartein in dichloromethane, yielding the chiral adduct (V). The ring-closing metathesis of (V) by means of a Ru catalyst in dichloromethane affords the chiral cyclopentenol derivative (VI), which is reduced to the (R,R)-5-(hydroxymethyl)-2-cyclopenten-1-ol (VII) by means of LiBH4 in THF. The reaction of diol (VII) with Ac2O; with methyl chloroformate, TEA and DMAP; or with ethyl chloroformate and pyridine gives the diacetate (VIII), the cyclic carbonate (IX) or the dicarbonate (X), respectively. The condensation of (VIII), (IX) or (X) with 2-amino-6-chloropurine (XI) by means of Pd(PPh3)4 yields the carbocyclic purines (XII), (XIII) or (XIV), respectively. Finally, these compounds are hydrolyzed with aqueous NaOH to the target carbocyclic guanine.
| 【1】 Crimmins, M.T.; et al.; An efficient, general asymmetric synthesis of carbocyclic nucleosides: Application of an asymmetric aldol/ring-closing metathesis strategy. J Org Chem 2000, 65, 25, 8499. |
| 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) | 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 |
| (II) | 17666 | 1,1-dimethylpropionic 4-pentenoic anhydride | C10H16O3 | 详情 | 详情 | |
| (III) | 17667 | (4S)-4-benzyl-3-(4-pentenoyl)-1,3-oxazolidin-2-one | C15H17NO3 | 详情 | 详情 | |
| (IV) | 17668 | acrylaldehyde; Acrolein | 107-02-8 | C3H4O | 详情 | 详情 |
| (V) | 17669 | (4S)-3-[(2S,3R)-2-allyl-3-hydroxy-4-pentenoyl]-4-benzyl-1,3-oxazolidin-2-one | C18H21NO4 | 详情 | 详情 | |
| (VI) | 17670 | (4S)-4-benzyl-3-[[(1S,2R)-2-hydroxy-3-cyclopenten-1-yl]carbonyl]-1,3-oxazolidin-2-one | C16H17NO4 | 详情 | 详情 | |
| (VII) | 17671 | (1R,5R)-5-(hydroxymethyl)-2-cyclopenten-1-ol | C6H10O2 | 详情 | 详情 | |
| (VIII) | 17674 | [(1R,2R)-2-(acetoxy)-3-cyclopenten-1-yl]methyl acetate | C10H14O4 | 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) | 17672 | [(1R,2R)-2-[(methoxycarbonyl)oxy]-3-cyclopenten-1-yl]methyl methyl carbonate | C10H14O6 | 详情 | 详情 | |
| (XI) | 11664 | 4-Chloro-3-nitroquinoline | C9H5ClN2O2 | 详情 | 详情 | |
| (XII) | 45424 | [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methyl acetate | C13H14ClN5O2 | 详情 | 详情 | |
| (XIII) | 17650 | [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol | C11H12ClN5O | 详情 | 详情 | |
| (XIV) | 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3
该中间体在本合成路线中的序号：(XXXI)4) The acylation of 4(S)-benzyloxazolidin-2-one (XXIV) with 4-pentenoyl pivaloyl anhydride (XXV) by means of NaH in THF gives 4(S)-benzyl-3-(4-pentenoyl)oxazolidin-2-one (XXVI), which is submitted to a diastereoselective syn aldol condensation with acrolein (XXVII), using dibutylboron triflate as catalyst, affording the aldol (XXVIII). The cyclization of (XXVIII) by means of the Grubbs catalyst in dichloromethane yields the cyclopentenol (XXIX), which is reduced with LiBH4 in THF/methanol to give the key intermediate 5(R)-(hydroxymethyl)-2-cyclopenten-1(R)-ol (XXX). The reaction of (XXX) with methyl chloroformate/pyridine/DMAP or methyl chloroformate/triethylamine/DMAP or acetic anhydride gives the diols (XXXI), (XXXII) and (XXXIII), respectively, each of which coupled with 2-amino-6-chloropurine (XXXIV) in the presence of NaH and palladium tetrakis(triphenylphosphine) in THF/DMSO, affords the purine intermediate (IX) already reported.
| 【1】 King, B.W.; Crimmins, M.T.; An efficient asymmetric approach to carbocyclic nucleosides: Asymmetric synthesis of 1592U89, a potent inhibitor of HIV reverse transcriptase. J Org Chem 1996, 61, 13, 4192-3. |
| 【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 |
|---|---|---|---|---|---|---|
| (IX) | 17650 | [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol | C11H12ClN5O | 详情 | 详情 | |
| (XXIV) | 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 |
| (XXV) | 17666 | 1,1-dimethylpropionic 4-pentenoic anhydride | C10H16O3 | 详情 | 详情 | |
| (XXVI) | 17667 | (4S)-4-benzyl-3-(4-pentenoyl)-1,3-oxazolidin-2-one | C15H17NO3 | 详情 | 详情 | |
| (XXVII) | 17668 | acrylaldehyde; Acrolein | 107-02-8 | C3H4O | 详情 | 详情 |
| (XXVIII) | 17669 | (4S)-3-[(2S,3R)-2-allyl-3-hydroxy-4-pentenoyl]-4-benzyl-1,3-oxazolidin-2-one | C18H21NO4 | 详情 | 详情 | |
| (XXIX) | 17670 | (4S)-4-benzyl-3-[[(1S,2R)-2-hydroxy-3-cyclopenten-1-yl]carbonyl]-1,3-oxazolidin-2-one | C16H17NO4 | 详情 | 详情 | |
| (XXX) | 17671 | (1R,5R)-5-(hydroxymethyl)-2-cyclopenten-1-ol | C6H10O2 | 详情 | 详情 | |
| (XXXI) | 17672 | [(1R,2R)-2-[(methoxycarbonyl)oxy]-3-cyclopenten-1-yl]methyl methyl carbonate | C10H14O6 | 详情 | 详情 | |
| (XXXII) | 17673 | (4aR,7aR)-4,4a,5,7a-tetrahydrocyclopenta[d][1,3]dioxin-2-one | C7H8O3 | 详情 | 详情 | |
| (XXXIII) | 17674 | [(1R,2R)-2-(acetoxy)-3-cyclopenten-1-yl]methyl acetate | C10H14O4 | 详情 | 详情 | |
| (XXXIV) | 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 |
合成路线4
该中间体在本合成路线中的序号：(X)An efficient asymmetric synthesis of abacavir has been reported: Acylation of the chiral oxazolidinone (I) with the mixed anhydride (II) by means of BuLi in THF gives the N-pentenoyloxazolidinone (III), which by condensation with acrolein (IV) catalyzed by TiCl4 and ()-spartein in dichloromethane yields the chiral adduct (V). The ring-closing metathesis of adduct (V) by means of the ruthenium catalyst (Cy3P)Cl2Ru=CHPh in dichloromethane affords the chiral cyclopentenol (VI), which is reduced to 5(R)-(hydroxymethyl)-2-cyclopenten-1(R)-ol (VII) by means of LiBH4 in THF. Reaction of diol (VII) with a) Ac2O, TEA and DMAP, b) methyl chloroformate, TEA and DMAP or c) methyl chloroformate, pyridine and DMAP gives a) the diacetate (VIII), b) the cyclic carbonate (IX) or c) the dicarbonate (X), respectively. The condensation of diacetate (VIII), cyclic carbonate (IX) or dicarbonate (X) with 2-amino-6-chloropurine (XI) by means of Pd(PPh3)4 yields the carbocyclic purines (XII), (XIII) or (XIV), respectively. Treatment of these chloro-purines (XII), (XIII) and (XIV) with cyclopropylamine (XV) in hot DMSO provides the corresponding cyclopropylaminopurine carbonate (XVI), abacavir or cyclopropylaminopurine acetate (XVII), respectively. Finally, the protecting groups of purines (XVI) and (XVII) are hydrolyzed with aqueous NaOH.
| 【1】 Crimmins, M.T.; et al.; An efficient, general asymmetric synthesis of carbocyclic nucleosides: Application of an asymmetric aldol/ring-closing metathesis strategy. J Org Chem 2000, 65, 25, 8499. |
| 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) | 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 |
| (II) | 17666 | 1,1-dimethylpropionic 4-pentenoic anhydride | C10H16O3 | 详情 | 详情 | |
| (III) | 17667 | (4S)-4-benzyl-3-(4-pentenoyl)-1,3-oxazolidin-2-one | C15H17NO3 | 详情 | 详情 | |
| (IV) | 17668 | acrylaldehyde; Acrolein | 107-02-8 | C3H4O | 详情 | 详情 |
| (V) | 17669 | (4S)-3-[(2S,3R)-2-allyl-3-hydroxy-4-pentenoyl]-4-benzyl-1,3-oxazolidin-2-one | C18H21NO4 | 详情 | 详情 | |
| (VI) | 17670 | (4S)-4-benzyl-3-[[(1S,2R)-2-hydroxy-3-cyclopenten-1-yl]carbonyl]-1,3-oxazolidin-2-one | C16H17NO4 | 详情 | 详情 | |
| (VII) | 17671 | (1R,5R)-5-(hydroxymethyl)-2-cyclopenten-1-ol | C6H10O2 | 详情 | 详情 | |
| (VIII) | 17674 | [(1R,2R)-2-(acetoxy)-3-cyclopenten-1-yl]methyl acetate | C10H14O4 | 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) | 17672 | [(1R,2R)-2-[(methoxycarbonyl)oxy]-3-cyclopenten-1-yl]methyl methyl carbonate | C10H14O6 | 详情 | 详情 | |
| (XI) | 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 |
| (XII) | 45424 | [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methyl acetate | C13H14ClN5O2 | 详情 | 详情 | |
| (XIII) | 17650 | [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol | C11H12ClN5O | 详情 | 详情 | |
| (XIV) | 45398 | [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methyl methyl carbonate | C13H14ClN5O3 | 详情 | 详情 | |
| (XV) | 12263 | Cyclopropylamine; Cyclopropanamine | 765-30-0 | C3H7N | 详情 | 详情 |
| (XVI) | 49433 | [(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopenten-1-yl]methyl acetate | C16H20N6O2 | 详情 | 详情 | |
| (XVII) | 49434 | [(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopenten-1-yl]methyl methyl carbonate | C16H20N6O3 | 详情 | 详情 |