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【结 构 式】 
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【分子编号】42659 【品名】(2R,3S,4S)-3-hydroxy-N-methoxy-5-[(4-methoxybenzyl)oxy]-N,2,4-trimethylpentanamide 【CA登记号】 |
【 分 子 式 】C17H27NO5 【 分 子 量 】325.40512 【元素组成】C 62.75% H 8.36% N 4.3% O 24.58% |
合成路线1
该中间体在本合成路线中的序号：(VII)The intermediate (XV) has been obtained as follows: The reaction of methyl 3-hydroxy-2(S)-methylpropionate (I) with 4-methoxybenzyl trichloroacetimidate gives methyl 3-(4-methoxybenzyloxy)-2(S)-methylpropionate (II), which is reduced with LiAlH4, yielding the primary alcohol (III). The Swern oxidation of (III) affords the aldehyde (IV), which is condensed with the chiral imidazolidinone (V) to provide the adduct (VI). The transamidation of (VI) with N,O-dimethylhydroxylamine by means of Me3Al gives the methoxyamide (VII), which is debenzylated with DDQ to yield the diol (VIII). The reaction of (VIII) with 4-methoxybenzaldehyde diethylacetal (IX) and CSA affords the cyclic ketal (X), which is condensed with the propionyloxazolidinone (XI) by means of dibutylboron triflate to furnish the adduct (XII). The silylation of the OH group of (XII) with Tbdms-OTf gives the silyl ether (XIII), which is reduced at the amide group with LiBH4 to yield the primary alcohol (XIV). Finally, this compound is treated with I2 and PPH3 to afford the intermediate iodo derivative (XV).
| 【1】 Smith, A.B. III; et al.; Gram-scale synthesis of (+)-discodermolide. Org Lett 1999, 1, 11, 1823. |
| 【2】 Smith, A.B. III; et al.; Evolution of a gram-scale synthesis of (+)-discodermolide. J Am Chem Soc 2000, 122, 36, 8654. |
| 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) | 17128 | Methyl (2S)-3-hydroxy-2-methylpropanoate | 72657-23-9 | C5H10O3 | 详情 | 详情 |
| (II) | 42654 | methyl (2S)-3-[(4-methoxybenzyl)oxy]-2-methylpropanoate | C13H18O4 | 详情 | 详情 | |
| (III) | 42655 | (2R)-3-[(4-methoxybenzyl)oxy]-2-methyl-1-propanol | C12H18O3 | 详情 | 详情 | |
| (IV) | 42656 | (2S)-3-[(4-methoxybenzyl)oxy]-2-methylpropanal | C12H16O3 | 详情 | 详情 | |
| (V) | 42657 | (4R,5S)-3-[(Z)-1-butoxy-1-propenyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one | C17H23NO3 | 详情 | 详情 | |
| (VI) | 42658 | (4R,5S)-3-[(2R,3S,4S)-3-hydroxy-5-[(4-methoxybenzyl)oxy]-2,4-dimethylpentanoyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one | C25H31NO6 | 详情 | 详情 | |
| (VII) | 42659 | (2R,3S,4S)-3-hydroxy-N-methoxy-5-[(4-methoxybenzyl)oxy]-N,2,4-trimethylpentanamide | C17H27NO5 | 详情 | 详情 | |
| (VIII) | 42660 | (2R,3S,4S)-3,5-dihydroxy-N-methoxy-N,2,4-trimethylpentanamide | C9H19NO4 | 详情 | 详情 | |
| (IX) | 35670 | 1-(diethoxymethyl)-4-methoxybenzene; 4-(diethoxymethyl)phenyl methyl ether | C12H18O3 | 详情 | 详情 | |
| (X) | 42661 | (2R)-N-methoxy-2-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-N-methylpropanamide | C17H25NO5 | 详情 | 详情 | |
| (XI) | 10968 | (4R)-3-Acetyl-4-benzyl-1,3-oxazolidin-2-one; (R)-(-)-3-Acetyl-4-benzyl-2-oxazolidinone | 184363-65-3 | C12H13NO3 | 详情 | 详情 |
| (XII) | 42662 | (4R)-4-benzyl-3-[(2R,3S,4S)-3-hydroxy-4-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-methylpentanoyl]-1,3-oxazolidin-2-one | C28H35NO7 | 详情 | 详情 | |
| (XIII) | 42663 | (4R)-4-benzyl-3-[(2R,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-methylpentanoyl]-1,3-oxazolidin-2-one | C34H49NO7Si | 详情 | 详情 | |
| (XIV) | 42664 | (2S,3R,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-methyl-1-pentanol | C24H42O5Si | 详情 | 详情 | |
| (XV) | 42665 | tert-butyl(dimethyl)silyl (1S,2R)-3-iodo-1-[(1R)-1-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]-2-methylpropyl ether; tert-butyl[((1S,2R)-3-iodo-1-[(1R)-1-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]-2-methylpropyl)oxy]dimethylsilane | C24H41IO4Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)The intermediate (XVIII) has been obtained as follows: The silylation of the intermediate methoxyamide (VII) with Tbdms-OTf gives the silylated methoxyamide (XVI), which is reduced with DIBAL yielding the aldehyde (XVII). Finally, this compound is condensed with ethyltriphenylphosphonium iodide and BuLi and treated with I2 and NaHMDS to afford the intermediate iodo derivative (XVIII). The intermediate (XXV) has been obtained as follows: The hydrogenolysis of intermediate (XVI) with H2 over Pd/C gives the primary alcohol (XIX), which is oxidized with SO3 and pyridine, yielding the aldehyde (XX). The condensation of (XX) with the silylated enol ether (XXI) by means of TiCl4 and TFA affords the lactone (XXII), which is reduced with K-Selectride to provide the chiral alcohol (XXIII). The silylation of (XXIII) with Tbdms-Cl and imidazole gives the silyl ether (XXIV), which is finally ozonolyzed with O3 and PPh3 to yield the target intermediate aldehyde (XXV).
| 【1】 Smith, A.B. III; et al.; Gram-scale synthesis of (+)-discodermolide. Org Lett 1999, 1, 11, 1823. |
| 【2】 Smith, A.B. III; et al.; Evolution of a gram-scale synthesis of (+)-discodermolide. J Am Chem Soc 2000, 122, 36, 8654. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 42659 | (2R,3S,4S)-3-hydroxy-N-methoxy-5-[(4-methoxybenzyl)oxy]-N,2,4-trimethylpentanamide | C17H27NO5 | 详情 | 详情 | |
| (XVI) | 42666 | (2R,3S,4S)-3-[[tert-butyl(dimethyl)silyl]oxy]-N-methoxy-5-[(4-methoxybenzyl)oxy]-N,2,4-trimethylpentanamide | C23H41NO5Si | 详情 | 详情 | |
| (XVII) | 42667 | (2R,3S,4S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-[(4-methoxybenzyl)oxy]-2,4-dimethylpentanal | C21H36O4Si | 详情 | 详情 | |
| (XVIII) | 42668 | tert-butyl(dimethyl)silyl (1R,2S,3Z)-4-iodo-1-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-2-methyl-3-pentenyl ether; tert-butyl[((1R,2S,3Z)-4-iodo-1-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-2-methyl-3-pentenyl)oxy]dimethylsilane | C23H39IO3Si | 详情 | 详情 | |
| (XIX) | 42669 | (2R,3S,4S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-N-methoxy-N,2,4-trimethylpentanamide | C15H33NO4Si | 详情 | 详情 | |
| (XX) | 42670 | (2R,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-N-methoxy-N,2,4-trimethyl-5-oxopentanamide | C15H31NO4Si | 详情 | 详情 | |
| (XXI) | 42671 | 3-methyl-1-methylene-2-butenyl trimethylsilyl ether; trimethyl[(3-methyl-1-methylene-2-butenyl)oxy]silane | C9H18OSi | 详情 | 详情 | |
| (XXII) | 42672 | (3R,4S,5R,6S)-4-methoxy-3,5-dimethyl-6-(4-methyl-2-oxo-3-pentenyl)tetrahydro-2H-pyran-2-one | C14H22O4 | 详情 | 详情 | |
| (XXIII) | 42673 | (3R,4S,5R,6S)-6-[(2S)-2-hydroxy-4-methyl-3-pentenyl]-4-methoxy-3,5-dimethyltetrahydro-2H-pyran-2-one | C14H24O4 | 详情 | 详情 | |
| (XXIV) | 42674 | (3R,4S,5R,6S)-6-((2S)-2-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-3-pentenyl)-4-methoxy-3,5-dimethyltetrahydro-2H-pyran-2-one | C20H38O4Si | 详情 | 详情 | |
| (XXV) | 42675 | (2S)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-[(2S,3R,4S,5R)-4-methoxy-3,5-dimethyl-6-oxotetrahydro-2H-pyran-2-yl]propanal | C17H32O5Si | 详情 | 详情 |