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【结 构 式】 
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【分子编号】38531 【品名】dimethoxy(phenyl)methyl methyl ether; 1-(trimethoxymethyl)benzene 【CA登记号】707-07-3 |
【 分 子 式 】C10H14O3 【 分 子 量 】182.21936 【元素组成】C 65.92% H 7.74% O 26.34% |
合成路线1
该中间体在本合成路线中的序号：(III)The asymmetric dihydroxylation of methyl cinnamate (I) with AD-alpha reagent in tert-butanol/water gives the (2R,3S)-dihydroxyester (II), which is treated with trimethyl orthobenzoate (III) and TsOH in dichloromethane yielding the benzoate (IV). This compound, without isolation, is treated with acetyl bromide affording (2S,3R)-2-(benzoyloxy)-3-bromo-3-phenylpropionic acid methyl ester (V), which is treated with sodium azide in DMF to give the corresponding (2R,3S)-azido compound (VI). Finally, this compound is reduced with H2 over Pd/C in methanol to the corresponding amine that suffers a benzoyl transposition yielding the target side chain (VII).
| 【1】 Hu, Z.; et al.; Utilization of a benzoyl migration to effect an expeditious synthesis of the paclitaxel C-13 side chain. Org Process Res Dev 1997, 1, 5, 387. |
| 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) | 23888 | methyl (E)-3-phenyl-2-propenoate | 103-26-4 | C10H10O2 | 详情 | 详情 |
| (II) | 38532 | methyl (2R,3S)-2,3-dihydroxy-3-phenylpropanoate | 122743-18-4 | C10H12O4 | 详情 | 详情 |
| (III) | 38531 | dimethoxy(phenyl)methyl methyl ether; 1-(trimethoxymethyl)benzene | 707-07-3 | C10H14O3 | 详情 | 详情 |
| (IV) | 38533 | (1R,2S)-2-hydroxy-1-(methoxycarbonyl)-2-phenylethyl benzoate | C17H16O5 | 详情 | 详情 | |
| (V) | 38534 | (1S,2R)-2-bromo-1-(methoxycarbonyl)-2-phenylethyl benzoate | C17H15BrO4 | 详情 | 详情 | |
| (VI) | 38535 | (1R,2S)-2-azido-1-(methoxycarbonyl)-2-phenylethyl benzoate | C17H15N3O4 | 详情 | 详情 | |
| (VII) | 63559 | methyl (2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoate | 32981-85-4 | C17H17NO4 | 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 reaction of cyclohexane-1,3,5-triol (I) with trimethyl orthobenzoate (II) by means of BF3/Et2O gives the cyclic orthoester (III), which is partially reduced with borane in THF to yield the alcohol (IV). Oxidation with Dess-Martin periodinane affords cyclohexanone (V), which is enantioselectively deprotonated with the chiral lithium (S,S')-alpha,alpha'-dimethyldibenzylamide (VI) in the presence of Tms-Cl in THF to provide the chiral silylated enol ether (VII). Ozonolysis of the double bond of (VII) gives the 6-oxohexanoic acid (VIII), which is reduced with NaBH4 to the corresponding hydroxyacid (IX). The methylation of (IX) with methyl iodide and K2CO3 yields the hydroxyester (X), which is oxidized with oxalyl chloride in DMSO to afford the oxoester (XI). The Wittig condensation of (XI) with decyltriphenylphosphonium bromide (XII) by means of BuLi in THF provides the unsaturated hexadecenoic ester (XIII), which is finally reduced, deprotected and cyclized by treatment with H2 over Pd/C in acetic acid to furnish the target (4S,6S)-4-hydroxy-6-undecyltetrahydrofuran-2-one (XIV). The conversion of (XIV) into tetrahydrolipstatin has already been described in scheme 11082304a.
| 【1】 Ono, S.; Endo, K.; Honda, T.; Construction of an enatiomerically pure 6-substituted 3,5-syn-dihydroxyhexanoic acid system by an enatioselective deprotonation strategy: Formal synthesis of an antiobesity agent, (-)-tetrahydrolipstatin. Chem Pharm Bull 2000, 48, 10, 1545. |
| 【2】 Ghosh, A.K.; Liu, C.; A stereoselective synthesis of (-)-tetrahydrolipstatin. Chem Commun (London) 1999, 1743. |
| 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) | 11800 | 1,3,5-Cyclohexanetriol; cis,cis-1,3,5-Cyclohexanetriol dihydrate | 50409-12-6 | C6H12O3 | 详情 | 详情 |
| (II) | 38531 | dimethoxy(phenyl)methyl methyl ether; 1-(trimethoxymethyl)benzene | 707-07-3 | C10H14O3 | 详情 | 详情 |
| (III) | 49608 | 3-phenyl-2,4,10-trioxatricyclo[3.3.1.1(3,7)]decane | C13H14O3 | 详情 | 详情 | |
| (IV) | 49609 | (1R,5S)-3-phenyl-2,4-dioxabicyclo[3.3.1]nonan-7-ol | C13H16O3 | 详情 | 详情 | |
| (V) | 49610 | (1R,5S)-3-phenyl-2,4-dioxabicyclo[3.3.1]nonan-7-one | C13H14O3 | 详情 | 详情 | |
| (VI) | 49611 | C16H18LiN | 详情 | 详情 | ||
| (VII) | 49612 | trimethyl[[(1S,3S,5R)-3-phenyl-2,4-dioxabicyclo[3.3.1]non-6-en-7-yl]oxy]silane; (1S,3S,5R)-3-phenyl-2,4-dioxabicyclo[3.3.1]non-6-en-7-yl trimethylsilyl ether | C16H22O3Si | 详情 | 详情 | |
| (VIII) | 49613 | 2-[(2S,4S,6R)-6-formyl-2-phenyl-1,3-dioxan-4-yl]acetic acid | C13H14O5 | 详情 | 详情 | |
| (IX) | 49614 | 2-[(2S,4S,6R)-6-(hydroxymethyl)-2-phenyl-1,3-dioxan-4-yl]acetic acid | C13H16O5 | 详情 | 详情 | |
| (X) | 49615 | methyl 2-[(2S,4S,6R)-6-(hydroxymethyl)-2-phenyl-1,3-dioxan-4-yl]acetate | C14H18O5 | 详情 | 详情 | |
| (XI) | 49616 | methyl 2-[(2S,4S,6R)-6-formyl-2-phenyl-1,3-dioxan-4-yl]acetate | C14H16O5 | 详情 | 详情 | |
| (XII) | 49618 | n-Decyl triphenylphosphonium bromide | 32339-43-8 | C28H36BrP | 详情 | 详情 |
| (XIII) | 49617 | methyl 2-[(2S,4S,6R)-2-phenyl-6-[(E)-1-undecenyl]-1,3-dioxan-4-yl]acetate | C24H36O4 | 详情 | 详情 | |
| (XIV) | 49598 | (4S,6S)-4-hydroxy-6-undecyltetrahydro-2H-pyran-2-one | C16H30O3 | 详情 | 详情 |