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【结 构 式】 
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【分子编号】61158 【品名】(1S,2S,3E)-1-{(E)-3-[(4R,6R)-4,6-dimethyl-1,3-dioxan-2-yl]-2-propenyl}-2-(methoxymethoxy)-4-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-3-butenyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate 【CA登记号】 |
【 分 子 式 】C27H39F6O10P 【 分 子 量 】668.5648412 【元素组成】C 48.51% H 5.88% F 17.05% O 23.93% P 4.63% |
合成路线1
该中间体在本合成路线中的序号：(XXXVII)The synthesis of the phosphonate intermediate (XXXVII) has been performed as follows: The reaction of the 2-hexynoic ester (XVIII) with Tbdps-Cl gives the silyl ether (XIX), which is reduced with DIBAL to yield the propargyl alcohol (XX). The protection of (XX) by reaction with dihydropyran affords the tetrahydropyranyl ether (XXI), which is selectively deprotected by means of DDQ to provide the acetylenic alcohol (XXII). The oxidation of (XXII) by means of SO3/pyridine, and NaClO2, followed by methylation with diazomethane gives the acetylenic ester (XXIII), which is condensed with phosphonate (XXIV) by means of BuLi to yield the chiral phosphonate (XXV). The condensation of (XXV) with 4-methyl-3,6-dihydro-2H-pyran-2(S)-carbaldehyde (XXVI) affords the ketonic adduct (XXVII), which is reduced with NaBH4 and CeCl3 to provide the secondary alcohol (XXVIII). The reaction of (XXVIII) with Mom-Cl gives the corresponding Mom-ether (XXIX), whose tetrahydropyranyl group is hydrolyzed by means of HCl to yield the primary alcohol (XXX). The selective monoreduction of the acetylenic triple bond of (XXX) by means of Red-Al affords the octadienyl alcohol (XXXI), which is oxidized with DMP to the expected aldehyde (XXXII). The reaction of (XXXII) with (R,R)-pentane-2,4-diol (XXXIII) affords the propylene ketal (XXXIV), which is desilylated by means of TBAF to provide the secondary alcohol (XXXV). The condensation of (XXXV) with the phosphonoacetic acid (XXXVI) furnishes the corresponding ester (XXXVII).
| 【1】 Ahmed, A.; Hoegenauer, E.K.; Enev, V.S.; Hanbauer, M.; Kaehlig, H.; Ohler, E.; Mulzer, J.; Total synthesis of the microtubule stabilizing antitumor agent laulimalide and some nonnatural analogues: The power of Sharpless' asymmetric epoxidation. J. Org. Chem. 2003, 68, 8, 3026. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVIII) | 61141 | propyl (5S)-5-hydroxy-6-[(4-methoxybenzyl)oxy]-2-hexynoate | C17H22O5 | 详情 | 详情 | |
| (XIX) | 61142 | propyl (5S)-5-{[tert-butyl(diphenyl)silyl]oxy}-6-[(4-methoxybenzyl)oxy]-2-hexynoate | C33H40O5Si | 详情 | 详情 | |
| (XX) | 61143 | (5S)-5-{[tert-butyl(diphenyl)silyl]oxy}-6-[(4-methoxybenzyl)oxy]-2-hexyn-1-ol | C30H36O4Si | 详情 | 详情 | |
| (XXI) | 61144 | tert-butyl{[(1S)-1-{[(4-methoxybenzyl)oxy]methyl}-5-(tetrahydro-2H-pyran-2-yloxy)-3-pentynyl]oxy}diphenylsilane; tert-butyl(diphenyl)silyl (1S)-1-{[(4-methoxybenzyl)oxy]methyl}-5-(tetrahydro-2H-pyran-2-yloxy)-3-pentynyl ether | C35H44O5Si | 详情 | 详情 | |
| (XXII) | 61145 | (2S)-2-{[tert-butyl(diphenyl)silyl]oxy}-6-(tetrahydro-2H-pyran-2-yloxy)-4-hexyn-1-ol | C27H36O4Si | 详情 | 详情 | |
| (XXIII) | 61146 | methyl (2S)-2-{[tert-butyl(diphenyl)silyl]oxy}-6-(tetrahydro-2H-pyran-2-yloxy)-4-hexynoate | C28H36O5Si | 详情 | 详情 | |
| (XXIV) | 13607 | dimethyl methylphosphonate | 756-79-6 | C3H9O3P | 详情 | 详情 |
| (XXV) | 61147 | dimethyl (3S)-3-{[tert-butyl(diphenyl)silyl]oxy}-2-oxo-7-(tetrahydro-2H-pyran-2-yloxy)-5-heptynylphosphonate | C30H41O7PSi | 详情 | 详情 | |
| (XXVI) | 61148 | (2S)-4-methyl-3,6-dihydro-2H-pyran-2-carbaldehyde | C7H10O2 | 详情 | 详情 | |
| (XXVII) | 61149 | (E,4S)-4-{[tert-butyl(diphenyl)silyl]oxy}-1-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-8-(tetrahydro-2H-pyran-2-yloxy)-1-octen-6-yn-3-one | C35H44O5Si | 详情 | 详情 | |
| (XXVIII) | 61150 | (E,3S,4S)-4-{[tert-butyl(diphenyl)silyl]oxy}-1-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-8-(tetrahydro-2H-pyran-2-yloxy)-1-octen-6-yn-3-ol | C35H46O5Si | 详情 | 详情 | |
| (XXIX) | 61151 | (5S,6S)-9,9-dimethyl-5-{(E)-2-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]ethenyl}-8,8-diphenyl-6-[4-(tetrahydro-2H-pyran-2-yloxy)-2-butynyl]-2,4,7-trioxa-8-siladecane; tert-butyl(diphenyl)silyl (1S)-1-{(1S,2E)-1-(methoxymethoxy)-3-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2-propenyl}-5-(tetrahydro-2H-pyran-2-yloxy)-3-pentynyl ether | C37H50O6Si | 详情 | 详情 | |
| (XXX) | 61152 | (5S,6S,7E)-5-{[tert-butyl(diphenyl)silyl]oxy}-6-(methoxymethoxy)-8-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-7-octen-2-yn-1-ol | C32H42O5Si | 详情 | 详情 | |
| (XXXI) | 61153 | (2E,5S,6S,7E)-5-{[tert-butyl(diphenyl)silyl]oxy}-6-(methoxymethoxy)-8-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2,7-octadien-1-ol | C32H44O5Si | 详情 | 详情 | |
| (XXXII) | 61154 | (2E,5S,6S,7E)-5-{[tert-butyl(diphenyl)silyl]oxy}-6-(methoxymethoxy)-8-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2,7-octadienal | C32H42O5Si | 详情 | 详情 | |
| (XXXIII) | 57935 | (2S,4S)-2,4-pentanediol | C5H12O2 | 详情 | 详情 | |
| (XXXIV) | 61155 | tert-butyl(diphenyl)silyl (1S,2S,3E)-1-{(E)-3-[(4R,6R)-4,6-dimethyl-1,3-dioxan-2-yl]-2-propenyl}-2-(methoxymethoxy)-4-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-3-butenyl ether; (5S,6S)-6-{(E)-3-[(4R,6R)-4,6-dimethyl-1,3-dioxan-2-yl]-2-propenyl}-9,9-dimethyl-5-{(E)-2-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]ethenyl}-8,8-diphenyl-2,4,7-trioxa-8-siladecane | C37H52O6Si | 详情 | 详情 | |
| (XXXV) | 61156 | (1E,3S,4S,6E)-7-[(4R,6R)-4,6-dimethyl-1,3-dioxan-2-yl]-3-(methoxymethoxy)-1-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-1,6-heptadien-4-ol | C21H34O6 | 详情 | 详情 | |
| (XXXVI) | 61157 | 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetic acid | C6H7F6O5P | 详情 | 详情 | |
| (XXXVII) | 61158 | (1S,2S,3E)-1-{(E)-3-[(4R,6R)-4,6-dimethyl-1,3-dioxan-2-yl]-2-propenyl}-2-(methoxymethoxy)-4-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-3-butenyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate | C27H39F6O10P | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXXVII)The condensation of the dihydropyranyl acetaldehyde intermediate (XVII) with the phosphonate (XXXVII) by means of KHMDS gives the open chain adduct (XXXVIII), which is cyclized by means of EtAlCl2 in dichloromethane to yield the macrolactone (XXXIX). The oxidation of the secondary OH group of (XXXIX) by means of DMP affords the ketone (XL), which is treated with TsOH in chloroform to provide the alcohol (XLI). The deprotection of the Mom-protecting group by means of Me2BBr in dichloromethane gives the dihydroxylated macrolactone (XLII), which is finally epoxidized by means of (+)-DIPT, t-BuOOH and Ti(i-PrO)4 to yield the target Laulimalide.
| 【1】 Ahmed, A.; Hoegenauer, E.K.; Enev, V.S.; Hanbauer, M.; Kaehlig, H.; Ohler, E.; Mulzer, J.; Total synthesis of the microtubule stabilizing antitumor agent laulimalide and some nonnatural analogues: The power of Sharpless' asymmetric epoxidation. J. Org. Chem. 2003, 68, 8, 3026. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVII) | 61140 | 2-((2R,6S)-6-{(2S)-2-methyl-4-[(trimethylsilyl)methyl]-4-pentenyl}-5,6-dihydro-2H-pyran-2-yl)acetaldehyde | C17H30O2Si | 详情 | 详情 | |
| (XXXVII) | 61158 | (1S,2S,3E)-1-{(E)-3-[(4R,6R)-4,6-dimethyl-1,3-dioxan-2-yl]-2-propenyl}-2-(methoxymethoxy)-4-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-3-butenyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate | C27H39F6O10P | 详情 | 详情 | |
| (XXXVIII) | 61159 | (1S,2S,3E)-1-{(E)-3-[(4R,6R)-4,6-dimethyl-1,3-dioxan-2-yl]-2-propenyl}-2-(methoxymethoxy)-4-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-3-butenyl (Z)-4-((2R,6S)-6-{(2S)-2-methyl-4-[(trimethylsilyl)methyl]-4-pentenyl}-5,6-dihydro-2H-pyran-2-yl)-2-buten | C40H64O8Si | 详情 | 详情 | |
| (XXXIX) | 61160 | (1R,7S,11S,15S,17S)-11-{[(1R,2S)-2-hydroxy-1-methylpropyl]oxy}-7-{(1S,2E)-1-(methoxymethoxy)-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 | C36H54O8 | 详情 | 详情 | |
| (XL) | 61161 | (1R,7S,11S,15S,17S)-7-{(1S,2E)-1-(methoxymethoxy)-3-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2-propenyl}-15-methyl-13-methylene-11-{[(1R)-1-methyl-2-oxopropyl]oxy}-6,21-dioxabicyclo[15.3.1]henicosa-3,9,19-trien-5-one | C36H52O8 | 详情 | 详情 | |
| (XLI) | 61162 | +(1R,7S,11S,15S,17S)-11-hydroxy-7-{(1S,2E)-1-(methoxymethoxy)-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 | C32H46O7 | 详情 | 详情 | |
| (XLII) | 61163 | (1R,7S,11S,15S,17S)-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 |