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【结 构 式】

【分子编号】37776

【品名】(1R,4S)-4-(benzoyloxy)-2-cyclopenten-1-yl benzoate

【CA登记号】

【 分 子 式 】C19H16O4

【 分 子 量 】308.33364

【元素组成】C 74.01% H 5.23% O 20.76%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(II)

A new enantioselective synthesis of neplanocin A has been reported: The enantiocontrolled condensation of the 6-chloropurine (I) with cis-1,3-bis(benzoyloxy)-4-cyclopentene (II) catalyzed by a chiral Pd catalyst gives the alkylated purine (III), which is condensed with the nitrosulfone (IV) by means of PPh3 and TEA yielding the intermediate (V). Epoxidation of (V) with MCPBA in dichloromethane affords the epoxide (VI), which is oxidized with O3 and DBU in methanol/THF giving the cyclopentenecarboxylate (VII). The esterification of the beta-OH group of (VII) with 4-nitrobenzoic acid (VIII), PPh3 and DEAD in THF, using a Mitsunobu reaction to invert the OH group, yields the ester (IX), with the desired alpha-OH configuration. The reduction of (IX) with DIBAL in THF/dichloromethane affords the unsaturated the diol (X), which is dihydroxylated with OsO4 and NMO in acetone/water providing the tetraol (XI). The reaction of (XI) with 2,2-dimethoxypropane and TsOH gives the diacetonide (XII), which is selectively monodeprotected with FeCl3 on silica gel yielding the dihydroxylated acetonide (XIII). The regioselective hydroxylation of the primary OH of (XIII) with pivaloyl chloride (Piv-Cl) in pyridine yields the pivalate (XIV), which is dehydrated with SOCl2 in DMF/pyridine affording the fully protected 6-chloropurine derivative (XV). Compound (XV) is treated with ammonia in order to eliminate the pivaloyl group and to form the adenine derivative (XVI), which is finally treated with hot aqueous HCl to eliminate the acetonide group.

1 Madsen, R.; Brown, B.; Guile, S.D.; Trost, B.M.; Palladium-catalyzed enantioselective synthesis of carbanucleosides. J Am Chem Soc 2000, 122, 25, 5947.
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) 17692 6-Chloropurine; 6-chloro-9H-purine 87-42-3 C5H3ClN4 详情 详情
(II) 37776 (1R,4S)-4-(benzoyloxy)-2-cyclopenten-1-yl benzoate C19H16O4 详情 详情
(III) 41036 (1S,4R)-4-(6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl benzoate C17H13ClN4O2 详情 详情
(IV) 37778 (nitromethyl)(dioxo)phenyl-lambda(6)-sulfane; nitromethyl phenyl sulfone 21272-85-5 C7H7NO4S 详情 详情
(V) 41037 6-chloro-9-[(1R,4S)-4-[(S)-nitro(phenylsulfonyl)methyl]-2-cyclopenten-1-yl]-9H-purine; (S)-[(1S,4R)-4-(6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl](nitro)methyl phenyl sulfone C17H14ClN5O4S 详情 详情
(VI) 41038 (S)-[(1S,2S,4R,5R)-4-(6-chloro-9H-purin-9-yl)-6-oxabicyclo[3.1.0]hex-2-yl](nitro)methyl phenyl sulfone; 6-chloro-9-[(1R,2R,4S,5S)-4-[(S)-nitro(phenylsulfonyl)methyl]-6-oxabicyclo[3.1.0]hex-2-yl]-9H-purine C17H14ClN5O5S 详情 详情
(VII) 41039 methyl (3S,4R)-4-(6-chloro-9H-purin-9-yl)-3-hydroxy-1-cyclopentene-1-carboxylate C12H11ClN4O3 详情 详情
(VIII) 18119 4-nitrobenzoic acid; p-nitrobenzoic acid 62-23-7 C7H5NO4 详情 详情
(IX) 41040 (1R,5R)-5-(6-chloro-9H-purin-9-yl)-3-(methoxycarbonyl)-2-cyclopenten-1-yl 4-nitrobenzoate C19H14ClN5O6 详情 详情
(X) 41041 (1R,5R)-5-(6-chloro-9H-purin-9-yl)-3-(hydroxymethyl)-2-cyclopenten-1-ol C11H11ClN4O2 详情 详情
(XI) 41042 (1S,2S,3S,4R)-4-(6-chloro-9H-purin-9-yl)-1-(hydroxymethyl)-1,2,3-cyclopentanetriol C11H13ClN4O4 详情 详情
(XII) 41043   C17H21ClN4O4 详情 详情
(XIII) 41044 (3aS,4S,6R,6aS)-6-(6-chloro-9H-purin-9-yl)-4-(hydroxymethyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol C14H17ClN4O4 详情 详情
(XIV) 41045 [(3aS,4S,6R,6aS)-6-(6-chloro-9H-purin-9-yl)-4-hydroxy-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methyl pivalate C19H25ClN4O5 详情 详情
(XV) 41046 [(3aR,6R,6aS)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyl-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methyl pivalate C19H23ClN4O4 详情 详情
(XVI) 41047 [(3aR,6R,6aS)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methanol C14H17N5O3 详情 详情

合成路线2

该中间体在本合成路线中的序号:(II)

The enantiocontrolled condensation of the protected guanine (I) with cis-1,3-bis(benzoyloxy)-4-cyclopentene (II) catalyzed by a chiral Pd catalyst gives the alkylated guanine (III), which is condensed with the nitrosulfone (IV) by means of PPh3 and TEA to yield the intermediate (V). The oxidation of (V) with oxone, tetramethylguanidine, and Na2CO3 in methanol/dichloromethane affords the cyclopentenecarboxylate (VI), which is finally reduced with calcium borohydride and deprotected with ammonia to provide the target compound.

1 Madsen, R.; Brown, B.; Guile, S.D.; Trost, B.M.; Palladium-catalyzed enantioselective synthesis of carbanucleosides. J Am Chem Soc 2000, 122, 25, 5947.
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) 37775 2-(acetamido)-9H-purin-6-yl diphenylcarbamate C20H16N6O3 详情 详情
(II) 37776 (1R,4S)-4-(benzoyloxy)-2-cyclopenten-1-yl benzoate C19H16O4 详情 详情
(III) 37777 (1S,4R)-4-(2-(acetamido)-6-[[(diphenylamino)carbonyl]oxy]-9H-purin-9-yl)-2-cyclopenten-1-yl benzoate C32H26N6O5 详情 详情
(IV) 37778 (nitromethyl)(dioxo)phenyl-lambda(6)-sulfane; nitromethyl phenyl sulfone 21272-85-5 C7H7NO4S 详情 详情
(V) 37779 2-(acetamido)-9-[(1R,4S)-4-[(S)-nitro(phenylsulfonyl)methyl]-2-cyclopenten-1-yl]-9H-purin-6-yl diphenylcarbamate C32H27N7O7S 详情 详情
(VI) 37780 methyl (1S,4R)-4-(2-(acetamido)-6-[[(diphenylamino)carbonyl]oxy]-9H-purin-9-yl)-2-cyclopentene-1-carboxylate C27H24N6O5 详情 详情

合成路线3

该中间体在本合成路线中的序号:(I)

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
Extended Information