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【结 构 式】 
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【分子编号】61197 【品名】(1R,7S,11S,15S,17R)-11-hydroxy-7-{(1S,2E)-1-hydroxy-3-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2-propenyl}-15-methyl-13-methylene-6,21-dioxabicyclo[15.3.1]henicosa-3,9,19-trien-5-one 【CA登记号】 |
【 分 子 式 】C30H42O6 【 分 子 量 】498.65988 【元素组成】C 72.26% H 8.49% O 19.25% |
合成路线1
该中间体在本合成路线中的序号：(XXXIX)Synthesis of the target compound: The condensation of the butenoic ester intermediate (VIII) with the intermediate octadienal derivative (XXXI) by means of (+)-Ipc2BCl , TEA and H2O2 in ethyl ether gives the linear adduct (XXXII), which is silylated with Tbdms-OTf and lutidine to yield the fully protected intermediate (XXXIII). The reduction of the ester group of (XXXIII) with DIBAL gives the alcohol (XXXIV), which is oxidized with DMP and NaClO2 to yield the carboxylic acid (XXXV). The selective deprotection of the Pmb ether of (XXXV) by means of DDQ in dichloromethane affords the hydroxyacid (XXXVI), which is submitted to cyclization by means of DEAD and PPh3 in benzene to provide the macrolactone (XXXVII). The methylenation of the ketonic group of (XXXVII) by reaction with Zn, PbI2, TiCl4 and CH2I2 in THF gives the exomethylene derivative (XXXVIII), which is desilylated by treatment with HF and pyridine in THF to yield the immediate precursor (XXXIX). Finally, this compound is selectively epoxidized by reaction with (+)-DIPT, tBuOOH and Ti(OiPr)4 in dichloromethane to afford the target Laulimalide
| 【1】 Paterson, I.; et al.; Total synthesis of the microtubule-stabilizing agent (-)-laulimalide. Org Lett 2001, 3, 20, 3149. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 61169 | methyl (Z)-4-{(2R,6R)-6-[(2R)-2-methyl-4-oxopentyl]-5,6-dihydro-2H-pyran-2-yl}-2-butenoate | C16H24O4 | 详情 | 详情 | |
| (XXXI) | 61189 | (2E,5R,6S,7E)-6-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4-methoxybenzyl)oxy]-8-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2,7-octadienal | C28H42O5Si | 详情 | 详情 | |
| (XXXII) | 61190 | methyl (Z)-4-((2R,6R)-6-{(2R,7E,10R,11S,12E)-11-{[tert-butyl(dimethyl)silyl]oxy}-6-hydroxy-10-[(4-methoxybenzyl)oxy]-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-oxo-7,12-tridecadienyl}-5,6-dihydro-2H-pyran-2-yl)-2-butenoate | C44H66O9Si | 详情 | 详情 | |
| (XXXIII) | 61191 | methyl (Z)-4-((2R,6R)-6-{(2R,7E,10R,11S,12E)-6,11-bis{[tert-butyl(dimethyl)silyl]oxy}-10-[(4-methoxybenzyl)oxy]-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-oxo-7,12-tridecadienyl}-5,6-dihydro-2H-pyran-2-yl)-2-butenoate | C50H80O9Si2 | 详情 | 详情 | |
| (XXXIV) | 61192 | (2R,7E,10R,11S,12E)-6,11-bis{[tert-butyl(dimethyl)silyl]oxy}-1-{(2R,6R)-6-[(Z)-4-hydroxy-2-butenyl]-3,6-dihydro-2H-pyran-2-yl}-10-[(4-methoxybenzyl)oxy]-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-7,12-tridecadien-4-one | C49H80O8Si2 | 详情 | 详情 | |
| (XXXV) | 61193 | (Z)-4-((2R,6R)-6-{(2R,7E,10R,11S,12E)-6,11-bis{[tert-butyl(dimethyl)silyl]oxy}-10-[(4-methoxybenzyl)oxy]-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-oxo-7,12-tridecadienyl}-5,6-dihydro-2H-pyran-2-yl)-2-butenoic acid | C49H78O9Si2 | 详情 | 详情 | |
| (XXXVI) | 61194 | (Z)-4-((2R,6R)-6-{(2R,7E,10R,11S,12E)-6,11-bis{[tert-butyl(dimethyl)silyl]oxy}-10-hydroxy-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-oxo-7,12-tridecadienyl}-5,6-dihydro-2H-pyran-2-yl)-2-butenoic acid | C41H70O8Si2 | 详情 | 详情 | |
| (XXXVII) | 61195 | (1R,7S,11S,15R,17R)-11-{[tert-butyl(dimethyl)silyl]oxy}-7-{(1S,2E)-1-{[tert-butyl(dimethyl)silyl]oxy}-3-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2-propenyl}-15-methyl-6,21-dioxabicyclo[15.3.1]henicosa-3,9,19-triene-5,13-dione | C41H68O7Si2 | 详情 | 详情 | |
| (XXXVIII) | 61196 | (1R,7S,11S,15S,17R)-11-{[tert-butyl(dimethyl)silyl]oxy}-7-{(1S,2E)-1-{[tert-butyl(dimethyl)silyl]oxy}-3-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2-propenyl}-15-methyl-13-methylene-6,21-dioxabicyclo[15.3.1]henicosa-3,9,19-trien-5-one | C42H70O6Si2 | 详情 | 详情 | |
| (XXXIX) | 61197 | (1R,7S,11S,15S,17R)-11-hydroxy-7-{(1S,2E)-1-hydroxy-3-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2-propenyl}-15-methyl-13-methylene-6,21-dioxabicyclo[15.3.1]henicosa-3,9,19-trien-5-one | C30H42O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XLIII)The diastereoselective condensation of the unsaturated aldehyde intermediate (XXXVI) with the acetylenic ester intermediate (XVI) by means of a chiral boron catalyst and TEA gives the aldol adduct (XXXVII), which is treated with Tbdms-Cl and imidazole to yield the silyl ether (XXXVIII). The stepwise deprotection of (XXXVIII) first with DDQ and then with Tms-OTf affords the acetylenic hydroxyacid (XXXIX), which is cyclized by means of 2,4,6-trichlorobenzoyl chloride and DIEA to provide the macrolactone (XL). The triple bond hydrogenation under Lindlar conditions (H2, Pd/CaCO3) gives the expected Z-alkene derivative (XLI). The reaction of the ketone group of (XLI) with CH2I2, Zn, PbCl2 and TiCl4 yields the methylenated compound (XLII), which is treated with HF and pyridine to eliminate the silyl protecting groups and afford the precursor (XLIII). Finally, compound (XLIII) is diastereoselectively epoxidated under Sharpless conditions (t-BuOOH, (+)-DIPT, and Ti(OiPr)4) to provide the target Laulimalide.
| 【1】 Nelson, S.G.; Cheung, W.S.; Kassick, A.J.; Hilfiker, M.A.; A de novo enantioselective total synthesis of (-)-laulimalide. J Am Chem Soc 2002, 124, 46, 13654. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 63902 | (1R,3S,7S,8S,10S,12S,18R)-7-hydroxy-12-{(1S,2E)-1-hydroxy-3-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2-propenyl}-3-methyl-5-methylene-9,13,22-trioxatricyclo[16.3.1.0~8,10~]docosa-15,19-dien-14-one | C30H42O7 | 详情 | 详情 | ||
| (XVI) | 63876 | tert-butyl 4-{(2R,6R)-6-[(2R)-2-methyl-4-oxopentyl]-5,6-dihydro-2H-pyran-2-yl}-2-butynoate | C19H28O4 | 详情 | 详情 | |
| (XXXVI) | 63897 | (2E,5S,6S,7E)-6-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4-methoxybenzyl)oxy]-8-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2,7-octadienal | C28H42O5Si | 详情 | 详情 | |
| (XXXVII) | 63898 | tert-butyl 4-((2R,6R)-6-{(2R,6S,7E,10S,11S,12E)-11-{[tert-butyl(dimethyl)silyl]oxy}-6-hydroxy-10-[(4-methoxybenzyl)oxy]-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-oxo-7,12-tridecadienyl}-5,6-dihydro-2H-pyran-2-yl)-2-butynoate | C47H70O9Si | 详情 | 详情 | |
| (XXXVIII) | 63900 | tert-butyl 4-((2R,6R)-6-{(2R,6S,7E,10S,11S,12E)-6,11-bis{[tert-butyl(dimethyl)silyl]oxy}-10-[(4-methoxybenzyl)oxy]-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-oxo-7,12-tridecadienyl}-5,6-dihydro-2H-pyran-2-yl)-2-butynoate | C53H84O9Si2 | 详情 | 详情 | |
| (XXXIX) | 63899 | 4-((2R,6R)-6-{(2R,6S,7E,10S,11S,12E)-6,11-bis{[tert-butyl(dimethyl)silyl]oxy}-10-hydroxy-2-methyl-13-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-4-oxo-7,12-tridecadienyl}-5,6-dihydro-2H-pyran-2-yl)-2-butynoic acid | C41H68O8Si2 | 详情 | 详情 | |
| (XL) | 63901 | (1R,7S,11S,15R,17R)-11-{[tert-butyl(dimethyl)silyl]oxy}-7-{(1S,2E)-1-{[tert-butyl(dimethyl)silyl]oxy}-3-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2-propenyl}-15-methyl-6,21-dioxabicyclo[15.3.1]henicosa-9,19-dien-3-yne-5,13-dione | C41H66O7Si2 | 详情 | 详情 | |
| (XLI) | 61195 | (1R,7S,11S,15R,17R)-11-{[tert-butyl(dimethyl)silyl]oxy}-7-{(1S,2E)-1-{[tert-butyl(dimethyl)silyl]oxy}-3-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2-propenyl}-15-methyl-6,21-dioxabicyclo[15.3.1]henicosa-3,9,19-triene-5,13-dione | C41H68O7Si2 | 详情 | 详情 | |
| (XLII) | 61196 | (1R,7S,11S,15S,17R)-11-{[tert-butyl(dimethyl)silyl]oxy}-7-{(1S,2E)-1-{[tert-butyl(dimethyl)silyl]oxy}-3-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2-propenyl}-15-methyl-13-methylene-6,21-dioxabicyclo[15.3.1]henicosa-3,9,19-trien-5-one | C42H70O6Si2 | 详情 | 详情 | |
| (XLIII) | 61197 | (1R,7S,11S,15S,17R)-11-hydroxy-7-{(1S,2E)-1-hydroxy-3-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2-propenyl}-15-methyl-13-methylene-6,21-dioxabicyclo[15.3.1]henicosa-3,9,19-trien-5-one | C30H42O6 | 详情 | 详情 |