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【结 构 式】 
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【分子编号】29720 【品名】[(dimethoxyphosphoryl)methyl]lithium 【CA登记号】 |
【 分 子 式 】C3H8LiO3P 【 分 子 量 】130.009482 【元素组成】C 27.72% H 6.2% Li 5.34% O 36.92% P 23.82% |
合成路线1
该中间体在本合成路线中的序号：(A)Treatment of the optically pure lactone (I) with lithium dimethyl methylphosphonate in tetrahydrofuran gives hemiacetal (II), which is oxidized to the diketone (III) using Jones' reagent in acetone. Then in the key step, compound (III) cyclizes to enone (IV) using potassium carbonate and 18-crown-6 in warm toluene. Lithium dimethyl cuprate addition to enone (IV) in ether gives ketone (V), which is converted to acid (VI) (a 1:1 mixture of E and Z olefins at C-5) using (4-carboxybutyl)triphenylphosphorane in dimethyl sulfoxide. Cleavage of the alcohol-protecting groups in (VI) with an acetic acid-water-tetrahydrofuran mixture followed by chromatography to remove the 5-E isomer affords 9-methylcarbacyclin (VII). Finally, treatment of (VII) with calcium oxide in tetrahydrofuran gives U-61431F (ciprostene calcium).
| 【1】 Aristoff, P.A.; Harrison, A.W.; Johnson, P.D.; Synthesis of 9-subtituted cabacyclin analogues. J Org Chem 1983, 48, 5341. |
| 【2】 Aristoff, P.A.; Practical synthesis of 6a-carbaprostaglandin I2. J Org Chem 1981, 46, 1954. |
| 【3】 Aristoff, P.A. (Pharmacia Corp.); Composition and process. US 4420632 . |
| 【4】 Aistoff, P.A.; Ciprostene Calcium. Drugs Fut 1985, 10, 11, 900. |
| 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) | 29762 | sodium 5-(triphenylphosphoranylidene)pentanoate | C23H22NaO2P | 详情 | 详情 | |
| (I) | 29757 | (3aR,4S,5R,6aS)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-4-[(E,3S)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]hexahydro-2H-cyclopenta[b]furan-2-one | C27H44O6 | 详情 | 详情 | |
| (II) | 29758 | dimethyl ((3aR,4S,5R,6aS)-2-hydroxy-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-4-[(E,3S)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]hexahydro-2H-cyclopenta[b]furan-2-yl)methylphosphonate | C30H53O9P | 详情 | 详情 | |
| (III) | 29759 | dimethyl 2-oxo-3-((4R,5R)-2-oxo-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-4-[(E,3S)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]tetrahydro-3-furanyl)propylphosphonate | C29H49O10P | 详情 | 详情 | |
| (IV) | 29760 | (3aR,4R,5R)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-4-[(E,3S)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-3a,4,5,6-tetrahydro-2(3H)-pentalenone | C28H44O5 | 详情 | 详情 | |
| (V) | 29761 | (3aR,5R,6R,6aR)-3a-methyl-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-6-[(E,3S)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]hexahydro-2(1H)-pentalenone | C29H48O5 | 详情 | 详情 | |
| (VI) | 29763 | 5-[(3aR,5R,6R,6aR)-3a-methyl-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-6-[(E,3S)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]hexahydro-2(1H)-pentalenylidene]pentanoic acid | C34H56O6 | 详情 | 详情 | |
| (VII) | 29764 | 5-[(3aS,5R,6R,6aR)-5-hydroxy-6-[(E,3S)-3-hydroxy-1-octenyl]-3a-methylhexahydro-2(1H)-pentalenylidene]pentanoic acid | C22H36O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(A)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3
该中间体在本合成路线中的序号：(V)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4
该中间体在本合成路线中的序号：(II)The reaction of N-(tert-butoxycarbonyl)-L-phenylalanine methyl ester (I) with trimethylphosphonate lithium salt (II) in THF gives the dimethyl L-phenylalanylmethylphosphonate (III), which is condensed with 2-phenylacetaldehyde (IV) by means of Na2CO3 in ethanol yielding the diphenylhexenone (V). The reduction of the carbonyl group of (V) with NaBH4 in methanol affords a diastereomeric mixture of alcohols (VI) and (VII) from which the desired major isomer (VII) is separated by column chromatography.. The epoxidation of the double bond of (VII) with MCPBA in dichloromethane gives the epoxide (VIII) (1), which is cleaved with Red-Al in THF providing the diol (IX). The reaction of (IX) with Ms-Cl and DIEA yields the intermediate dimesylate (X) which, without isolation, affords oxazolidinone (XI). The reaction of (XI) with sodium azide and 18-C-6 in DMSO gives the azide (XII), which is treated with NaH and Boc2O in THF in order to cleave the oxazolidine ring and furnish the protected aminoalcohol (XIII). Finally the azido group of (XIII) is hydrogenate with H2 over Pd/C in methanol to afford the monoprotected diaminoalcohol (XIV) the target compound.
| 【1】 Norbedo, S.; Benedetti, F.; Epoxyalcohol route to hydroxyethylene dipeptide isosteres: A new synthesis of the diaminoalcohol core of HIV-protease inhibitor ABT-538 (ritonavir). Chem Commun (London) 2001, 2, 203. |
| 【2】 Benedetti, F.; et al.; Versatile and stereoselective synthesis of diamino diol dipeptide isosteres, core units of pseudopeptide HIV protease inhibitors. J Org Chem 1997, 62, 26, 9348. |
| 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) | 21673 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoate | C15H21NO4 | 详情 | 详情 | |
| (II) | 29720 | [(dimethoxyphosphoryl)methyl]lithium | C3H8LiO3P | 详情 | 详情 | |
| (III) | 47117 | dimethyl (3S)-3-[(tert-butoxycarbonyl)amino]-2-oxo-4-phenylbutylphosphonate | C17H26NO6P | 详情 | 详情 | |
| (IV) | 18456 | 2-phenylacetaldehyde | 122-78-1 | C8H8O | 详情 | 详情 |
| (V) | 47118 | tert-butyl (1S,3E)-1-benzyl-2-oxo-5-phenyl-3-pentenylcarbamate | C23H27NO3 | 详情 | 详情 | |
| (VI) | 47119 | tert-butyl (1S,2S,3E)-1-benzyl-2-hydroxy-5-phenyl-3-pentenylcarbamate | C23H29NO3 | 详情 | 详情 | |
| (VII) | 47120 | tert-butyl (1S,2R,3E)-1-benzyl-2-hydroxy-5-phenyl-3-pentenylcarbamate | C23H29NO3 | 详情 | 详情 | |
| (VIII) | 47121 | tert-butyl (1S,2S)-1-benzyl-2-[(2R,3S)-3-benzyloxiranyl]-2-hydroxyethylcarbamate | C23H29NO4 | 详情 | 详情 | |
| (IX) | 47122 | tert-butyl (1S,2R,4R)-1-benzyl-2,4-dihydroxy-5-phenylpentylcarbamate | C23H31NO4 | 详情 | 详情 | |
| (X) | 47123 | (1R,3R)-1-[(1S)-1-[(3,3-dimethylbutanoyl)amino]-2-phenylethyl]-3-[(methylsulfonyl)oxy]-4-phenylbutyl methanesulfonate | C26H37NO7S2 | 详情 | 详情 | |
| (XI) | 47124 | (1R)-1-benzyl-2-[(4S,5S)-4-benzyl-2-oxo-1,3-oxazolidin-5-yl]ethyl methanesulfonate | C20H23NO5S | 详情 | 详情 | |
| (XII) | 47125 | (4S,5S)-5-[(2S)-2-azido-3-phenylpropyl]-4-benzyl-1,3-oxazolidin-2-one | C19H20N4O2 | 详情 | 详情 | |
| (XIII) | 47126 | tert-butyl (1S,2S,4S)-4-azido-1-benzyl-2-hydroxy-5-phenylpentylcarbamate | C23H30N4O3 | 详情 | 详情 | |
| (XIV) | 47127 | tert-butyl (1S,2S,4S)-4-amino-1-benzyl-2-hydroxy-5-phenylpentylcarbamate | C23H32N2O3 | 详情 | 详情 |