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【结 构 式】 
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【分子编号】63897 【品名】(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 【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：(XXXVI)Synthesis of the target Laulimalide. The condensation of the tin derivative (XXVI) with the chiral isopropenyl boron derivative (XXVII) gives the secondary alcohol (XXVIII), which is alkylated with allyl bromide (XXIX) and KHMDS to yield the allyl ether (XXX). The ring closing metathesis reaction in (XXX) by means of Schrock catalyst affords the dihydropyranyl stannane (XXXI), which is treated with N-iodosuccinimide to provide the iodovinyl compound (XXXII). The reaction of (XXXII) with BuLi and MgBr2 gives the vinylmagnesium derivative (XXXIII), which is condensed with the unsaturated aldehyde intermediate (XXV) to yield the olefinic alcohol (XXXIV). The reaction of (XXXIV) with Tbdms-Cl and imidazole affords the silyl ether (XXXV), which is selectively deprotected with formic acid, and oxidated with DMP to provide the chiral unsaturated aldehyde (XXXVI).
| 【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 |
|---|---|---|---|---|---|---|
| (XXV) | 63887 | (2S,4E)-2-[(4-methoxybenzyl)oxy]-6-(trityloxy)-4-hexenal | C33H32O4 | 详情 | 详情 | |
| (XXVI) | 63888 | (E)-3-(tributylstannyl)-2-propenal | C15H30OSn | 详情 | 详情 | |
| (XXVII) | 63889 | C5H11B | 详情 | 详情 | ||
| (XXVIII) | 63890 | (1E)-5-methyl-1-(tributylstannyl)-1,5-hexadien-3-ol | C19H38OSn | 详情 | 详情 | |
| (XXIX) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (XXX) | 63891 | [(1E)-3-(allyloxy)-5-methyl-1,5-hexadienyl](tributyl)stannane; allyl 3-methyl-1-[(E)-2-(tributylstannyl)ethenyl]-3-butenyl ether | C22H42OSn | 详情 | 详情 | |
| (XXXI) | 63894 | tributyl{(E)-2-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]ethenyl}stannane | C20H38OSn | 详情 | 详情 | |
| (XXXII) | 63893 | (2S)-2-[(E)-2-iodoethenyl]-4-methyl-3,6-dihydro-2H-pyran | C8H11IO | 详情 | 详情 | |
| (XXXIII) | 63892 | bromo{(E)-2-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]ethenyl}magnesium | C8H11BrMgO | 详情 | 详情 | |
| (XXXIV) | 63895 | (1E,3S,4S,6E)-4-[(4-methoxybenzyl)oxy]-1-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-8-(trityloxy)-1,6-octadien-3-ol | C41H44O5 | 详情 | 详情 | |
| (XXXV) | 63896 | tert-butyl(dimethyl)silyl (1S,2S,4E)-2-[(4-methoxybenzyl)oxy]-1-{(E)-2-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]ethenyl}-6-(trityloxy)-4-hexenyl ether; tert-butyl{[(1S,2S,4E)-2-[(4-methoxybenzyl)oxy]-1-{(E)-2-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]ethenyl}-6-(trityloxy)-4-hexenyl]oxy}dimethylsilane | C47H58O5Si | 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 |
合成路线2
该中间体在本合成路线中的序号：(XXXVI)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 |