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【结 构 式】

【分子编号】29721

【品名】dimethyl [6-(benzyloxy)-4-hydroxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methylphosphonate

【CA登记号】

【 分 子 式 】C17H25O8P

【 分 子 量 】388.354462

【元素组成】C 52.58% H 6.49% O 32.96% P 7.98%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(II)

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
Extended Information