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【结 构 式】 
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【分子编号】45398 【品名】[(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methyl methyl carbonate 【CA登记号】 |
【 分 子 式 】C13H14ClN5O3 【 分 子 量 】323.73876 【元素组成】C 48.23% H 4.36% Cl 10.95% N 21.63% O 14.83% |
合成路线1
该中间体在本合成路线中的序号：(X)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：(XVI)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3
该中间体在本合成路线中的序号：(VIII)The reaction of cyclopentadiene (I) with tosyl cyanide in acidic water gives the racemic bicyclic lactam (II), which is opened by means of TsCl and NaH to yield cis-3-(tosylamino)-4-cyclopentene-1-carboxylic acid (III). The reduction of (III) with NaBH4 affords the corresponding carbinol (IV), which is acylated with Ac2O and pyridine to provide the acetate (V). The reaction of (V) with Ts-Cl and NaH yields the ditosylamino derivative (VI), which is condensed with 2-amino-6-chloropurine (VII) by means of a Pd catalyst, affording the carbocyclic purine (VIII). Finally, this compound is hydrolyzed with hot aqueous NaOH to give the target carbocyclic guanine.
| 【1】 Jung, M.E.; Rhee, H.; pi-Allylpalladium formation from allylic amines via N,N-ditosylimides and N-tosylamides: Efficient synthesis of the antiviral agent carbovir. J Org Chem 1994, 59, 17, 4719. |
| 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) | 33410 | cis-2-azabicyclo[2.2.1]hept-5-en-3-one | C6H7NO | 详情 | 详情 | |
| (III) | 45408 | (1S,4R)-4-[[(4-methylphenyl)sulfonyl]amino]-2-cyclopentene-1-carboxylic acid | C13H15NO4S | 详情 | 详情 | |
| (IV) | 45409 | N-[(1R,4S)-4-(hydroxymethyl)-2-cyclopenten-1-yl]-4-methylbenzenesulfonamide | C13H17NO3S | 详情 | 详情 | |
| (V) | 45410 | ((1S,4R)-4-[[(4-methylphenyl)sulfonyl]amino]-2-cyclopenten-1-yl)methyl acetate | C15H19NO4S | 详情 | 详情 | |
| (VI) | 45411 | ((1S,4R)-4-[bis[(4-methylphenyl)sulfonyl]amino]-2-cyclopenten-1-yl)methyl acetate | C22H25NO6S2 | 详情 | 详情 | |
| (VII) | 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 |
| (VIII) | 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4
该中间体在本合成路线中的序号：(IX)The addition of HCl to cyclopentadiene (I) gives 3-chlorocyclopentene (II), which is converted to racemic 2-cyclopentene-1-carboxylic acid (III). Optical resolution of (II) by crystallization of its (-)-1-phenylethylamine yields the desired enantiomer (IV), which is reduced with LiAlH4 in ethyl ether affording the chiral carbinol (V) (ee 98%). The reaction of (V) successively with BuLi, CO2 and I2 provides the iodinated cyclic carbonate (VI), which is treated with DBU in hot toluene to give the unsaturated cyclic carbonate (VII). The condensation of (VII) with 2-amino-6-chloropurine (VIII) by means of a Pd catalyst yields the carbocyclic purine (IX), which is finally hydrolyzed with aqueous NaOH to afford the target carbocyclic guanine. Alternatively, carbinol (V) can also be obtained by the vitamin B12/Zn/NH4Cl-catalyzed isomerization of 1,2-epoxycyclopentane (X) to the chiral cyclopentenol (XI), which by a [2,3]-sigmatropic Wittig rearrangement with KH, ICH2-SnBu4 and BuLi yields the target carbinol (V). However, the enantiomeric excess obtained is only ee 54%.
| 【1】 Hildbrand, S.; et al.; A short synthesis of (-)-carbovir. Helv Chim Acta 1994, 77, 5, 1236. |
| 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) | 19541 | 3-chloro-1-cyclopentene | C5H7Cl | 详情 | 详情 | |
| (III) | 45419 | 2-cyclopentene-1-carboxylic acid | C6H8O2 | 详情 | 详情 | |
| (IV) | 45420 | (1S)-2-cyclopentene-1-carboxylic acid | C6H8O2 | 详情 | 详情 | |
| (V) | 45421 | (1S)-2-cyclopenten-1-ylmethanol | C6H10O | 详情 | 详情 | |
| (VI) | 45422 | (4aR,7S,7aS)-7-iodohexahydrocyclopenta[d][1,3]dioxin-2-one | C7H9IO3 | 详情 | 详情 | |
| (VII) | 17673 | (4aR,7aR)-4,4a,5,7a-tetrahydrocyclopenta[d][1,3]dioxin-2-one | C7H8O3 | 详情 | 详情 | |
| (VIII) | 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 |
| (IX) | 45398 | [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methyl methyl carbonate | C13H14ClN5O3 | 详情 | 详情 | |
| (X) | 38011 | 6-oxabicyclo[3.1.0]hexane | 285-67-6 | C5H8O | 详情 | 详情 |
| (XI) | 45423 | (1R)-2-cyclopenten-1-ol | C5H8O | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XIV)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6
该中间体在本合成路线中的序号：(XIV)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 |