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【结 构 式】 
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【药物名称】Neplanocin A 【化学名称】[1R-(1alpha,2alpha,3beta)]-3-(6-Amino-9H-purin-9-yl)-5-(hydroxymethyl)-4-cyclopentene-1,2-diol 【CA登记号】156407-85-1 【 分 子 式 】C11H13N5O3 【 分 子 量 】263.25796 |
【开发单位】Toyo Jozo (Originator) 【药理作用】ONCOLYTIC DRUGS |
合成路线1
A new synthesis of neplanocin A has been reported: The triphenylmethyl (Tr) ether of 2,3-O-(isopropylidene)-D-ribose (I) is reduced with LiAlH4 to the corresponding diol, which without isolation is partially protected with tert-butyldimethylsilyl chloride (TBDMS-Cl) to yield the secondary alcohol (II). The oxidation of (II) with oxalyl chloride affords the ketone (III), which is alkylated with the lithium derivative of trimethylsilyl (TMS) diazomethane in THF to give the carbene intermediate (IV), which cyclizes to the cyclopentene (V). The partial deprotection of (V) followed by oxidation with pyridinium dichromate (PDC) yields the cyclopentenone (VI), which is reduced with LiAlH4 in THF to the cyclopentanol (VII) as a single stereoisomer. The condensation of (VII) with adenine (VIII) under Mitsunobu's conditions (triphenylphosphine and diethylazodicarboxylate [DEAD]) in THF affords protected neplanocin A (VIII), which is finally deprotected with HCl in methanol.
| 【1】 Ohira, S.; Sawamoto, T.; Yamato, M.; Synthesis of (-)-neplanocin A via C-H insertion of alkylidenecarbene. Tetrahedron Lett 1995, 36, 9, 1537. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 62992 | [diazo(trimethylsilyl)methyl]lithium | C4H9LiN2Si | 详情 | 详情 | ||
| (I) | 10336 | (3aR,4S,6R,6aR)-2,2-Dimethyl-6-[(trityloxy)methyl]tetrahydrofuro[3,4-d][1,3]dioxol-4-ol | C27H28O5 | 详情 | 详情 | |
| (II) | 10337 | (1R)-1-[(4R,5S)-5-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(trityloxy)-1-ethanol | C33H44O5Si | 详情 | 详情 | |
| (III) | 10338 | 1-[(4S,5S)-5-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(trityloxy)-1-ethanone | C33H42O5Si | 详情 | 详情 | |
| (IV) | 62991 | 2-[(4R,5S)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-propen-1-ol | C9H16O4 | 详情 | 详情 | |
| (V) | 10340 | ((3aR,6aR)-6-[[tert-Butyl(dimethyl)silyl]oxy]-2,2-dimethyl-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl trityl ether; ([(3aR,6aR)-2,2-Dimethyl-6-[(trityloxy)methyl]-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]oxy)(tert-butyl)dimethylsilane | C34H42O4Si | 详情 | 详情 | |
| (VI) | 10341 | (3aR,6aR)-2,2-Dimethyl-6-[(trityloxy)methyl]-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-one | C28H26O4 | 详情 | 详情 | |
| (VII) | 10342 | (3aS,4S,6aR)-2,2-Dimethyl-6-[(trityloxy)methyl]-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol | C28H28O4 | 详情 | 详情 | |
| (VIII) | 10343 | 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine | 73-24-5 | C5H5N5 | 详情 | 详情 |
合成路线2
A new synthesis of neplanocin A has been reported: The ring opening of 2',3'-O-isopropylideneadenine (I) with diisobutylaluminum hydride (DIBAL) in THF gives (2S,3R,4R)-9-[4,5-dihydroxy-2,3-(isopropylidenedioxy)pentyl]adenosine (II), which is partially protected with tert-butyldimethylsilyl chloride (TBDMS-Cl) and imidazole in DMF yielding the monosilylated compound (III). The Dess-Martin oxidation of (III) in dichloromethane affords the correponding ketone (IV), which is cyclized with the lithium derivative of the trimethylsilyl diazomethane in THF/hexane to give the proteced compound 2,3-O-isopropylidene-4'-O-(tert-butyldimethylsilyl)neplanocin A (V). Finally, this compound is deprotected by the usual deprotection methods.
| 【1】 Niizuma, S.; Matsuda, A.; Shuto, S.; New neplanocin analogues. 10. The conversion of adenosine to neplanocin A, a carbocyclic nucleoside antibiotic with potent antiviral activity. Tetrahedron 1997, 53, 40, 13621. |
| 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) | 17560 | [(3aR,4R,6R,6aS)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methanol | 362-75-4 | C13H17N5O4 | 详情 | 详情 |
| (II) | 17561 | (1R)-1-[(4R,5R)-5-[(6-amino-9H-purin-9-yl)methyl]-2,2-dimethyl-1,3-dioxolan-4-yl]-1,2-ethanediol | C13H19N5O4 | 详情 | 详情 | |
| (III) | 17562 | (1R)-1-[(4R,5R)-5-[(6-amino-9H-purin-9-yl)methyl]-2,2-dimethyl-1,3-dioxolan-4-yl]-2-[[tert-butyl(dimethyl)silyl]oxy]-1-ethanol | C19H33N5O4Si | 详情 | 详情 | |
| (IV) | 17563 | 1-[(4S,5R)-5-[(6-amino-9H-purin-9-yl)methyl]-2,2-dimethyl-1,3-dioxolan-4-yl]-2-[[tert-butyl(dimethyl)silyl]oxy]-1-ethanone | C19H31N5O4Si | 详情 | 详情 | |
| (V) | 17564 | 9-[(3aR,4R,6aR)-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-9H-purin-6-ylamine | C20H31N5O3Si | 详情 | 详情 |
合成路线3
The reaction of (-)-5-O-benzyl-2,3-O-isopropylidene-D-ribolactonle (I) with lithium dimethylmethylphosphonate in THF gives the hemiketal (II) in quantitative yield. Benzoylation of (II) with benzoyl chloride in pyridine leads to the acyclic dibenzoate (III), which is debenzoylated with methanolic sodium methoxide to afford the beta-ketophosphonate (IV). Oxidation of (IV) with the modified Collins' reagent (CrO3 - 2Py) in dichloromethane gives diketophosphonate (V). The reaction of (V) with powdered anhydrous potassium carbonate and 18-crown-6-ether in benzene under high dilution gives the 2-cyclopentenone (VI) (50% yield). Reduction of (VI) with sodium borohydride in a 0.4-M CeCl3 - 7H2O- methanol solution affords the allylic alcohol (VII) (85% yield), which is mesylated to give (VIII). The mesyl group on (VIII) is displaced by lithium azide to give the beta-azide (IX) (84% yield). Reduction of (IX) with 1,3-propanedithiol and triethylamine in absolute methanol gives the 2-cyclopentenylamine (X) (85% yield). Condensation of (X) with 5-amino-4,6-dichloropyrimidine in the presence of triethylamine (n-BuOH, reflux, 45 h) gives (XI) (52% yield). Ring closure with triethyl orthoformate and Ac2O or HCl gives (XII), which is treated with methanolic ammonia to afford (XIII) (overall yield 58%). Debenzylation of (XIII) with boron trichloride in dichloromethane leads to removal of the isopropylidene group (61% yield). Another method to obtain neplanocin A is also available, in which an enantioselective synthesis of neplanocin A is performed by a chemoenzymatic approach starting from the Diels-Alder adduct of cyclopentadiene and dimethyl acetylene-dicarboxylate.
| 【1】 Arita, M.; Ito, Y.; Sawai, H.; Ohno, M.; Adachi, K.; Enantioselective synthesis of the carbocyclic nucleosides (-)-aristeromycin and (-)-neplanocin A by a chemicoenzymatic approach. J Am Chem Soc 1983, 105, 4049. |
| 【2】 Lim, M.I.; Maquez, V.E.; Total synthesis of (-)-neplanocin A. Tetrahedron Lett 1981, 34, 4, 359-366. |
| 【3】 Hayashi, M.; Yoshioka, H.; Yaginuma, S.; Nakatsu, K.; Studies on neplanocin A, new antitumor antibiotic. II. Structure determination. J Antibiot 1981, 34, 6, 675-680. |
| 【4】 Fujimoto, S.; Neplanocin A. Drugs Fut 1985, 10, 10, 822. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 29720 | [(dimethoxyphosphoryl)methyl]lithium | C3H8LiO3P | 详情 | 详情 | |
| (B) | 29729 | 1,3-propanedithiol; 3-sulfanylpropylhydrosulfide | 109-80-8 | C3H8S2 | 详情 | 详情 |
| (I) | 29719 | 6-(benzyloxy)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one | C14H16O5 | 详情 | 详情 | |
| (II) | 29721 | dimethyl [6-(benzyloxy)-4-hydroxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methylphosphonate | C17H25O8P | 详情 | 详情 | |
| (III) | 29722 | (1R)-1-[(4S,5S)-5-[(E)-1-(benzoyloxy)-2-(dimethoxyphosphoryl)ethenyl]-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(benzyloxy)ethyl benzoate | C32H35O10P | 详情 | 详情 | |
| (IV) | 29723 | dimethyl 2-[(4R,5R)-5-[(1R)-2-(benzyloxy)-1-hydroxyethyl]-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxoethylphosphonate | C18H27O8P | 详情 | 详情 | |
| (V) | 29724 | dimethyl 2-[(4R,5S)-5-[2-(benzyloxy)acetyl]-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxoethylphosphonate | C18H25O8P | 详情 | 详情 | |
| (VI) | 29725 | 6-(benzyloxy)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-one | C15H16O4 | 详情 | 详情 | |
| (VII) | 29726 | (4S)-6-(benzyloxy)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol | C15H18O4 | 详情 | 详情 | |
| (VIII) | 29727 | (4S)-6-(benzyloxy)-2,2-dimethyl-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxole; benzyl (6S)-2,2-dimethyl-6-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl ether | C18H24O4S | 详情 | 详情 | |
| (IX) | 29728 | (6R)-6-azido-2,2-dimethyl-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl benzyl ether; (4R)-4-azido-6-(benzyloxy)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxole | C15H17N3O3 | 详情 | 详情 | |
| (X) | 29730 | (4R)-6-(benzyloxy)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ylamine; (4R)-6-(benzyloxy)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-amine | C15H19NO3 | 详情 | 详情 | |
| (XI) | 29731 | N-(5-amino-6-chloro-4-pyrimidinyl)-N-[6-(benzyloxy)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]amine; N(4)-[6-(benzyloxy)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-6-chloro-4,5-pyrimidinediamine | C19H21ClN4O3 | 详情 | 详情 | |
| (XII) | 29732 | 9-[6-(benzyloxy)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-6-chloro-9H-purine; benzyl 6-(6-chloro-9H-purin-9-yl)-2,2-dimethyl-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl ether | C20H19ClN4O3 | 详情 | 详情 | |
| (XIII) | 29733 | 9-[6-(benzyloxy)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-9H-purin-6-amine; 9-[6-(benzyloxy)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-9H-purin-6-ylamine | C20H21N5O3 | 详情 | 详情 | |
| (C) | 22845 | 5-Amino-4,6-dichloropyrimidine; 4,6-dichloro-5-pyrimidinylamine; 4,6-dichloro-5-pyrimidinamine | 5413-85-4 | C4H3Cl2N3 | 详情 | 详情 |
合成路线4
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5
The reaction of D-ribose (I) with 2,2-dimethoxypropane (II) by means of HClO4 in methanol gives the isopropylidene derivative (III), which is oxidized with PCC in benzene to yield the tetrahydrofuranone (IV). The reaction of (IV) with the lithium salt of dimethyl methylphosphonate (V) affords the chiral cyclopentenone (VI), which is condensed with tert-butyl methyl ether (VII) by means of tBu-OK and sec-BuLi in THF to provide the cyclopentenol derivative (VIII). The reaction of (VIII) with Ac2O, TEA and DMAP in dichloromethane gives the corresponding acetate (IX), which is submitted to rearrangement catalyzed by PdCl2(acetonitrile)2 and benzoquinone in refluxing THF to yield the regioisomeric acetate (X). The hydrolysis of (X) by means of K2CO3 in methanol yields the corresponding alcohol (XI), which is condensed with 6-chloropurine (XII) by means of PPh3 and DIEA to afford the adduct (XIII). The reaction of (XIII) with ammonia in ethanol at 80 C in a steel bomb affords the protected adenine nucleoside (XIV), which is finally deprotected with aqueous TFA to provide the target cyclopentenyl nucleoside.
| 【1】 Ali, S.M.; et al.; Efficient enantioselective syntheses of carbocyclic nucleoside and prostaglandin synthons. Tetrahedron Lett 1990, 31, 11, 1509. |
| 【2】 Song, G.Y.; et al.; Enantiomeric synthesis of D-and L-cyclopentenyl nucleosides and their antiviral activity against HIV and West Nile virus. J Med Chem 2001, 44, 23, 3985. |
| 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) | 10016 | D-Ribose; (3R,4S,5R)-5-(Hydroxymethyl)tetrahydro-2,3,4-furantriol; (2R,3R,4R)-2,3,4,5-Tetrahydroxypentanal | 50-69-1 | C5H10O5 | 详情 | 详情 |
| (II) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (III) | 49594 | Methyl 2,3-O-Isopropylidene-beta-D-Ribofuranoside | C9H16O5 | 详情 | 详情 | |
| (IV) | 49585 | (3aS,6aR)-6-methoxy-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one | C8H12O5 | 详情 | 详情 | |
| (V) | 29720 | [(dimethoxyphosphoryl)methyl]lithium | C3H8LiO3P | 详情 | 详情 | |
| (VI) | 49586 | (3aS,6aS)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-one | C8H10O3 | 详情 | 详情 | |
| (VII) | 49587 | 2-methoxy-2-methylpropane; tert-butyl methyl ether | C5H12O | 详情 | 详情 | |
| (VIII) | 49588 | tert-Butylmethyl ether; Methyl tert-butyl ether | 1634-04-4 | C13H22O4 | 详情 | 详情 |
| (IX) | 49589 | (3aS,4S,6aS)-4-(tert-butoxymethyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl acetate | C15H24O5 | 详情 | 详情 | |
| (X) | 49590 | (3aR,4S,6aR)-6-(tert-butoxymethyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl acetate | C15H24O5 | 详情 | 详情 | |
| (XI) | 49591 | (3aS,4S,6aR)-6-(tert-butoxymethyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol | C13H22O4 | 详情 | 详情 | |
| (XII) | 17692 | 6-Chloropurine; 6-chloro-9H-purine | 87-42-3 | C5H3ClN4 | 详情 | 详情 |
| (XIII) | 49592 | 9-[(3aS,4R,6aR)-6-(tert-butoxymethyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-6-chloro-9H-purine; [(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 tert-butyl ether | C18H23ClN4O3 | 详情 | 详情 | |
| (XIV) | 49593 | 9-[(3aS,4R,6aR)-6-(tert-butoxymethyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-9H-purin-6-amine; 9-[(3aS,4R,6aR)-6-(tert-butoxymethyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-9H-purin-6-ylamine | C18H25N5O3 | 详情 | 详情 |
合成路线6
The monoprotection of acetonide dol (I) by means of Pmb-Cl and KOH in refluxing benzene gives the alcohol (II), which is submitted to a Swern oxidation, yielding the aldehyde (III). The Horner Wadswort Emmons condensation of (III) with phosphonate (IV) by means of NaH in THF affords the unsaturated ester (V), which is deprotected by means of HCl in hot ethanol to provide the diol (VI), which is reprotected by means of Tbdms-OTf and TEA in dichloromethane to gives the bis silyl ether (VII).The selective deprotection of (VII) by means of DDQ in aqueous acetonitrile yields the primary alcohol (VIII), which is submitted to a Swern oxidation to afford the corresponding aldehyde (IX). The cyclization of (IX) by means of PhCH2-S-Li in THF provides the chiral cyclopentanol (X), which is desilylated by means of HF in aqueous acetonitrile to give the trihydroxy compound (XI). The vicinal cis diols of (XI) are selectively protected with acetone and Ts-OH to yield the acetonide (XII), which is desulfurized by oxidation with NaIO4 and heating at 180 C in decalin to afford the cyclopentenol (XIII). The oxidation of (XIII) by means of PDC in dichloromethane provides the cyclopentenone (XIV), which is reduced at the ester and ketone groups by means of DIBAL in toluene to give the diol (XV). The selective silylation of the primary OH group of (XV) by means of Tbdms-Cl, TEA and DMAP in dichloromethane yields the primary silyl ether (XVI), which is condensed with adenine (XVII) by means of DIAD and PPH3 in THF to afford the protected adduct (XVIII). Finally this compound is deprotected by means of HCl in methanol to provide the target Neplanocin A.
| 【1】 Ono, M.; et al.; Total synthesis of (-)-neplanocin A by using lithium thiolate-initiated Michael-aldol tandem cyclization reaction. J Org Chem 2001, 66, 24, 8199. |
| 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) | 52911 | [(4R,5R)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol | C7H14O4 | 详情 | 详情 | |
| (II) | 58117 | ((4R,5R)-5-{[(4-methoxybenzyl)oxy]methyl}-2,2-dimethyl-1,3-dioxolan-4-yl)methanol | C15H22O5 | 详情 | 详情 | |
| (III) | 58118 | (4S,5R)-5-{[(4-methoxybenzyl)oxy]methyl}-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde | C15H20O5 | 详情 | 详情 | |
| (IV) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (V) | 58119 | ethyl (E)-3-((4R,5R)-5-{[(4-methoxybenzyl)oxy]methyl}-2,2-dimethyl-1,3-dioxolan-4-yl)-2-propenoate | C19H26O6 | 详情 | 详情 | |
| (VI) | 58120 | ethyl (E,4R,5R)-4,5-dihydroxy-6-[(4-methoxybenzyl)oxy]-2-hexenoate | C16H22O6 | 详情 | 详情 | |
| (VII) | 58121 | ethyl (E,4R,5R)-4,5-bis{[tert-butyl(dimethyl)silyl]oxy}-6-[(4-methoxybenzyl)oxy]-2-hexenoate | C28H50O6Si2 | 详情 | 详情 | |
| (VIII) | 58122 | ethyl (E,4R,5R)-4,5-bis{[tert-butyl(dimethyl)silyl]oxy}-6-hydroxy-2-hexenoate | C20H42O5Si2 | 详情 | 详情 | |
| (IX) | 58123 | ethyl (E,4R,5S)-4,5-bis{[tert-butyl(dimethyl)silyl]oxy}-6-oxo-2-hexenoate | C20H40O5Si2 | 详情 | 详情 | |
| (X) | 58124 | ethyl (1S,2R,3S,4R,5R)-2-(benzylsulfanyl)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-hydroxycyclopentanecarboxylate | C27H48O5SSi2 | 详情 | 详情 | |
| (XI) | 58125 | ethyl (1S,2R,3S,4R,5R)-2-(benzylsulfanyl)-3,4,5-trihydroxycyclopentanecarboxylate | C15H20O5S | 详情 | 详情 | |
| (XII) | 58126 | ethyl (3aR,4S,5R,6S,6aS)-5-(benzylsulfanyl)-6-hydroxy-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxole-4-carboxylate | C18H24O5S | 详情 | 详情 | |
| (XIII) | 58127 | ethyl (3aR,6R,6aS)-6-hydroxy-2,2-dimethyl-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxole-4-carboxylate | C11H16O5 | 详情 | 详情 | |
| (XIV) | 58128 | ethyl (3aR,6aR)-2,2-dimethyl-6-oxo-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxole-4-carboxylate | C11H14O5 | 详情 | 详情 | |
| (XV) | 58129 | (3aS,4S,6aR)-6-(hydroxymethyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol | C9H14O4 | 详情 | 详情 | |
| (XVI) | 58130 | (3aS,4S,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol | C15H28O4Si | 详情 | 详情 | |
| (XVII) | 10343 | 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine | 73-24-5 | C5H5N5 | 详情 | 详情 |
| (XVIII) | 58131 | 9-[(3aS,4R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-9H-purin-6-ylamine; 9-[(3aS,4R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-9H-purin-6-amine | C20H31N5O3Si | 详情 | 详情 |