|
【结 构 式】 
|
【分子编号】61189 【品名】(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 【CA登记号】 |
【 分 子 式 】C28H42O5Si 【 分 子 量 】486.72398 【元素组成】C 69.1% H 8.7% O 16.44% Si 5.77% |
合成路线1
该中间体在本合成路线中的序号：(XXXI)The intermediate octadienal derivative (XXXI) has been obtained as follows: The selective monosilylation of 3(R),4-dihydroxybutyric acid methyl ester (XIV) by means of Tbdms-Cl and imidazole in dichloromethane gives the terminal silyl ether (XV), which is treated with PmbOC(=NH)CCl3 and TfOH in ethyl ether to yield the fully protected compound (XVI). The reduction of the ester group of (XVI) by means of LiAlH4 in THF affords the butanol derivative (XVII), which is subjected to Dess-Martin oxidation to furnish the corresponding aldehyde (XVIII). The condensation of (XVIII) with phosphonate (XIX) by means of DIEA and LiCl in acetonitrile provides the hexenoic ester (XX), which is reduced with DIBAL to the corresponding unsaturated alcohol (XXI). The reaction of (XXI) with Tbdps-Cl and imidazole gives the silyl ether (XXII), which is selectively monodesilylated by means of TsOH in ethanol to yield the alcohol (XXIII). The Swern oxidation of (XXIII) affords the corresponding aldehyde (XXIV), which is methylated with MeMgCl to provide the secondary alcohol (XXV). The Swern oxidation of (XXXV) yields the methyl ketone (XXVI), which is condensed with the intermediate 4-methyl-3,6-dihydro-2H-pyran-2(S)-carbaldehyde (XIII) by means of (cHex)2BCl and TEA, followed by a treatment with MsCl and TEA to afford the octadienone (XXVII). The reduction of (XXVII) by means of Zn(BH4)2 in ethyl ether provides the octadienol (XXVIII), which is silylated with Tbdms-OTf and lutidine to give the silyl ether (XXIX). The selective monodeprotection of (XXIX) by means of TBAF in AcOH yields the octadienol (XXX), which is oxidized with DMP to afford the intermediate octadienal derivative (XXXI)
| 【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 |
|---|---|---|---|---|---|---|
| (XIII) | 61148 | (2S)-4-methyl-3,6-dihydro-2H-pyran-2-carbaldehyde | C7H10O2 | 详情 | 详情 | |
| (XIV) | 11807 | methyl (3S)-3,4-dihydroxybutanoate | C5H10O4 | 详情 | 详情 | |
| (XV) | 61174 | methyl (3R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxybutanoate | C11H24O4Si | 详情 | 详情 | |
| (XVI) | 61175 | methyl (3R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-[(4-methoxybenzyl)oxy]butanoate | C19H32O5Si | 详情 | 详情 | |
| (XVII) | 61176 | (3R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-[(4-methoxybenzyl)oxy]-1-butanol | C18H32O4Si | 详情 | 详情 | |
| (XVIII) | 61177 | (3R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-[(4-methoxybenzyl)oxy]butanal | C18H30O4Si | 详情 | 详情 | |
| (XX) | 61178 | methyl (E,5R)-6-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4-methoxybenzyl)oxy]-2-hexenoate | C21H34O5Si | 详情 | 详情 | |
| (XXI) | 61179 | (E,5R)-6-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4-methoxybenzyl)oxy]-2-hexen-1-ol | C20H34O4Si | 详情 | 详情 | |
| (XXII) | 61180 | (E,9R)-9-[(4-methoxybenzyl)oxy]-2,2,12,12,13,13-hexamethyl-3,3-diphenyl-4,11-dioxa-3,12-disila-6-tetradecene; tert-butyl(dimethyl)silyl (2R,4E)-6-{[tert-butyl(diphenyl)silyl]oxy}-2-[(4-methoxybenzyl)oxy]-4-hexenyl ether | C36H52O4Si2 | 详情 | 详情 | |
| (XXIII) | 61181 | (2R,4E)-6-{[tert-butyl(diphenyl)silyl]oxy}-2-[(4-methoxybenzyl)oxy]-4-hexen-1-ol | C30H38O4Si | 详情 | 详情 | |
| (XXIV) | 61182 | (2R,4E)-6-{[tert-butyl(diphenyl)silyl]oxy}-2-[(4-methoxybenzyl)oxy]-4-hexenal | C30H36O4Si | 详情 | 详情 | |
| (XXV) | 61183 | (3R,5E)-7-{[tert-butyl(diphenyl)silyl]oxy}-3-[(4-methoxybenzyl)oxy]-5-hepten-2-ol | C31H40O4Si | 详情 | 详情 | |
| (XXVI) | 61184 | (3R,5E)-7-{[tert-butyl(diphenyl)silyl]oxy}-3-[(4-methoxybenzyl)oxy]-5-hepten-2-one | C31H38O4Si | 详情 | 详情 | |
| (XXVII) | 61185 | (1E,4R,6E)-8-{[tert-butyl(diphenyl)silyl]oxy}-4-[(4-methoxybenzyl)oxy]-1-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-1,6-octadien-3-one | C38H46O5Si | 详情 | 详情 | |
| (XXVIII) | 61186 | (1E,3S,4R,6E)-8-{[tert-butyl(diphenyl)silyl]oxy}-4-[(4-methoxybenzyl)oxy]-1-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-1,6-octadien-3-ol | C38H48O5Si | 详情 | 详情 | |
| (XXIX) | 61187 | (E,9R,10S)-9-[(4-methoxybenzyl)oxy]-2,2,12,12,13,13-hexamethyl-10-{(E)-2-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]ethenyl}-3,3-diphenyl-4,11-dioxa-3,12-disila-6-tetradecene; tert-butyl(dimethyl)silyl (1S,2R,4E)-6-{[tert-butyl(diphenyl)silyl]oxy}-2-[(4-methoxybenzyl)oxy]-1-{(E)-2-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]ethenyl}-4-hexenyl ether | C44H62O5Si2 | 详情 | 详情 | |
| (XXX) | 61188 | (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-octadien-1-ol | C28H44O5Si | 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 |
合成路线2
该中间体在本合成路线中的序号：(XXXI)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 |