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【结 构 式】 
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【分子编号】42608 【品名】[(1R,3S,4S)-4-aminospiro[2.2]pent-1-yl]methanol 【CA登记号】 |
【 分 子 式 】C6H11NO 【 分 子 量 】113.15948 【元素组成】C 63.69% H 9.8% N 12.38% O 14.14% |
合成路线1
该中间体在本合成路线中的序号：(I)The intermediate (XLIII) has been obtained in two related ways: 1) The protection of (2S,3S,4S)-2,4-dimethyl-1-(tert-butyldimethylsilyloxy)-5-hexen-3-ol (I) with p-methoxybenzyl bromide and NaH gives the benzyl ether (XXXIV) which is ozonolyzed with O3, yielding the aldehyde (XXXV), which is condensed with the phosphonium salt (XXXVI) by means of KHMDS to afford the iodovinyl derivative (XXXVII). The homologation of (XXXVII) with vinylzinc bromide (XXXVIII) provides the octadiene derivative (XXXIX), which is desilylated with TFA, furnishing the primary alcohol (XL). The oxidation of (XL) with DMP gives the aldehyde (XLI), which is treated with CH3-MgBr, yielding the secondary alcohol (XLII). Finally, this alcohol is oxidized with DMP to the target intermediate ketone (XLIII). 2) The protection of (2S,3R,4S)-2,4-dimethyl-1-(tert-butyldimethylsilyloxy)-5-hexen-3-ol (XVII) with p-methoxybenzyl bromide and NaH gives the benzyl ether (XLIV), which is ozonolyzed with O3, yielding the aldehyde (XLV). The reaction of (XLV) with CH3-MgBr affords the secondary alcohol (XLVI), which is desilylated with TFA.
| 【1】 Hung, D.T.; et al.; Syntheses of discodermolides useful for investigating microtubule binding and stabilization. J Am Chem Soc 1996, 118, 45, 11054. |
| 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) | 42608 | [(1R,3S,4S)-4-aminospiro[2.2]pent-1-yl]methanol | C6H11NO | 详情 | 详情 | |
| (XXXIV) | 42717 | tert-butyl([(2S,3S,4S)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5-hexenyl]oxy)dimethylsilane; tert-butyl(dimethyl)silyl (2S,3S,4S)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5-hexenyl ether | n/a | C22H38O3Si | 详情 | 详情 |
| (XXXV) | 42628 | (2R,3R,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-3-[(4-methoxybenzyl)oxy]-2,4-dimethylpentanal | C21H36O4Si | 详情 | 详情 | |
| (XXXVI) | 42718 | (iodomethyl)(triphenyl)phosphonium iodide | n/a | C19H17I2P | 详情 | 详情 |
| (XXXVII) | 42719 | tert-butyl([(2S,3S,4S,5Z)-6-iodo-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5-hexenyl]oxy)dimethylsilane; tert-butyl(dimethyl)silyl (2S,3S,4S,5Z)-6-iodo-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5-hexenyl ether | n/a | C22H37IO3Si | 详情 | 详情 |
| (XXXVIII) | 42720 | bromo(vinyl)zinc | n/a | C2H3BrZn | 详情 | 详情 |
| (XXXIX) | 42630 | tert-butyl([(2S,3S,4S,5Z)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5,7-octadienyl]oxy)dimethylsilane; tert-butyl(dimethyl)silyl (2S,3S,4S,5Z)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5,7-octadienyl ether | C24H40O3Si | 详情 | 详情 | |
| (XL) | 42631 | (2S,3S,4S,5Z)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5,7-octadien-1-ol | C18H26O3 | 详情 | 详情 | |
| (XLI) | 42632 | (2R,3S,4S,5Z)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5,7-octadienal | C18H24O3 | 详情 | 详情 | |
| (XLII) | 42721 | (3S,4S,5S,6Z)-4-[(4-methoxybenzyl)oxy]-3,5-dimethyl-6,8-nonadien-2-ol | C19H28O3 | 详情 | 详情 | |
| (XLIII) | 42722 | (3R,4S,5S,6Z)-4-[(4-methoxybenzyl)oxy]-3,5-dimethyl-6,8-nonadien-2-one | C19H26O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)Zinc-catalyzed debromination of dibromo compound (I) afforded the methylene cyclopropane (II). After reduction of the ester group of (II) with LiAlH4, the resulting alcohol (III) was converted to acetate ester (IV) with Ac2O in pyridine. The carbene generated from ethyl diazoacetate in the presence of rhodium catalyst was then added to the olefinic double bond of (IV) to furnish the spirocyclopentane derivative (V) as a mixture of four stereoisomers. Hydrolysis of (V) with NaOH gave rise to the corresponding mixture of stereoisomeric hydroxy acids, which were partially separated by column chromatography to provide a mixture of proximal (VI) and medial-syn (VII) isomers. Acetylation of alcohols (VI) and (VII) gave the corresponding mixture of diastereoisomeric acetates (VIIIa-b). Curtius rearrangement of (VIIIa-b) employing diphenylphosphoryl azide in tert-butanol produced the tert-butyl carbamates (IXa-b). After deacetylation of (IX) using K2CO3 in aqueous MeOH, separation of the isomers by means of column chromatography furnished the desired medial-syn carbamate (X). Removal of the Boc group o (X) was accomplished with HCl in methanol to give the corresponding amine hydrochloride (XI). The purine derivative (XIV) was obtained by alkylation of amine (XI) with 4,6-dichloro-5-nitropyrimidine (XII), followed by treatment of the crude nitro amine (XIII) with SnCl2 and triethyl orthoformate. Cloropurine (XIV) was then converted into adenine derivative (XV) by ammonolysis with methanolic ammonia at 100 C in an autoclave. This was finally coupled with phenyl chlorophosphoroalaninate (XVI) to furnish the title compound.
| 【1】 Guan, H.-P.; Drach, J.C.; Cheng, Y.-C.; Kern, E.R.; Ksebati, M.B.; Zemlicka, J.; Spiropentane mimics of nucleosides: Analogues of 2'-deoxyadenosine and 2'-deoxyguanosine. Synthesis of all stereoisomers, isomeric assignment, and biological activity. J Org Chem 2000, 65, 5, 1280. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIIa) | 42603 | (1S,3S,4S)-4-[(acetoxy)methyl]spiro[2.2]pentane-1-carboxylic acid | C9H12O4 | 详情 | 详情 | |
| (VIIIb) | 42604 | (1S,3S,4R)-4-[(acetoxy)methyl]spiro[2.2]pentane-1-carboxylic acid | C9H12O4 | 详情 | 详情 | |
| (IXa) | 42605 | [(1R,3S,4S)-4-[(tert-butoxycarbonyl)amino]spiro[2.2]pent-1-yl]methyl acetate | C13H21NO4 | 详情 | 详情 | |
| (IXb) | 42606 | [(1S,3S,4S)-4-[(tert-butoxycarbonyl)amino]spiro[2.2]pent-1-yl]methyl acetate | C13H21NO4 | 详情 | 详情 | |
| (I) | 42613 | ethyl 2-bromo-2-(bromomethyl)cyclopropanecarboxylate | C7H10Br2O2 | 详情 | 详情 | |
| (II) | 21769 | ethyl 2-methylenecyclopropanecarboxylate | C7H10O2 | 详情 | 详情 | |
| (III) | 42598 | (2-methylenecyclopropyl)methanol | C5H8O | 详情 | 详情 | |
| (IV) | 42599 | (2-methylenecyclopropyl)methyl acetate | C7H10O2 | 详情 | 详情 | |
| (V) | 42600 | ethyl 4-[(acetoxy)methyl]spiro[2.2]pentane-1-carboxylate | C11H16O4 | 详情 | 详情 | |
| (VI) | 42601 | (1S,3S,4S)-4-(hydroxymethyl)spiro[2.2]pentane-1-carboxylic acid | C7H10O3 | 详情 | 详情 | |
| (VII) | 42602 | (1S,3S,4R)-4-(hydroxymethyl)spiro[2.2]pentane-1-carboxylic acid | C7H10O3 | 详情 | 详情 | |
| (X) | 42607 | tert-butyl (1S,3S,4R)-4-(hydroxymethyl)spiro[2.2]pent-1-ylcarbamate | C11H19NO3 | 详情 | 详情 | |
| (XI) | 42608 | [(1R,3S,4S)-4-aminospiro[2.2]pent-1-yl]methanol | C6H11NO | 详情 | 详情 | |
| (XII) | 15284 | 4,6-dichloro-5-nitropyrimidine | 4316-93-2 | C4HCl2N3O2 | 详情 | 详情 |
| (XIII) | 42609 | [(1R,3S,4S)-4-[(6-chloro-5-nitro-4-pyrimidinyl)amino]spiro[2.2]pent-1-yl]methanol | C10H11ClN4O3 | 详情 | 详情 | |
| (XIV) | 42610 | [(1R,3S,4S)-4-(6-chloro-9H-purin-9-yl)spiro[2.2]pent-1-yl]methanol | C11H11ClN4O | 详情 | 详情 | |
| (XV) | 42611 | [(1R,3S,4S)-4-(6-amino-9H-purin-9-yl)spiro[2.2]pent-1-yl]methanol | C11H13N5O | 详情 | 详情 | |
| (XVI) | 42612 | methyl 2-[[chloro(phenoxy)phosphoryl]amino]propanoate | C10H13ClNO4P | 详情 | 详情 |