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【结 构 式】 
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【分子编号】63876 【品名】tert-butyl 4-{(2R,6R)-6-[(2R)-2-methyl-4-oxopentyl]-5,6-dihydro-2H-pyran-2-yl}-2-butynoate 【CA登记号】 |
【 分 子 式 】C19H28O4 【 分 子 量 】320.42892 【元素组成】C 71.22% H 8.81% O 19.97% |
合成路线1
该中间体在本合成路线中的序号：(XVI)The acetylenic ester intermediate (XVI) has been obtained as follows. The reaction of acetaldehyde (I) with acetyl bromide (II) by means of a chiral Al catalyst gives lactone (III), which is condensed with N,O-dimethylhydroxylamine (IV) to yield the Weinreb amide (V). The reduction of (V) with iBu2AlH affords the chiral butyraldehyde (VI), which is condensed with acetyl bromide (II) and DIEA to provide the lactone (VII). The reaction of (VII) with methylmagnesium bromide gives the chiral pentanoic acid (VIII), which is reduced with BH3/Me2S and reoxidated with PCC to yield the aldehyde (IX). The condensation of (IX) with acetyl bromide (II) and DIEA affords the lactone (X), which is treated with the lithium salt (XI) to provide the dihydropyranone (XII). The reduction of (XII) with NaBH4 and CeCl3, followed by reaction with Ac2O and TEA gives the acetoxy derivative (XIII), which is desilylated with TBAF and oxidized with PDC to yield the methyl ketone (XIV). Finally, the condensation of (XIV) with the allenic tributyl tin derivative (XV) by means of Bu3Sn-OTf in dichloromethane affords the target acetylenic ester intermediate (XVI).
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 11974 | Acetaldehyde | 75-07-0 | C2H4O | 详情 | 详情 |
| (II) | 63866 | acetyl bromide | C2H3BrO | 详情 | 详情 | |
| (III) | 63867 | (4R)-4-methyl-2-oxetanone | C4H6O2 | 详情 | 详情 | |
| (IV) | 13361 | (Methoxyamino)methane; N,O-Dimethylhydroxylamine | 1117-97-1 | C2H7NO | 详情 | 详情 |
| (V) | 63868 | (3R)-3-{[tert-butyl(diphenyl)silyl]oxy}-N-methoxy-N-methylbutanamide | C22H31NO3Si | 详情 | 详情 | |
| (VI) | 63871 | (3R)-3-{[tert-butyl(diphenyl)silyl]oxy}butanal | C20H26O2Si | 详情 | 详情 | |
| (VII) | 63870 | (4R)-4-((2R)-2-{[tert-butyl(diphenyl)silyl]oxy}propyl)-2-oxetanone | C22H28O3Si | 详情 | 详情 | |
| (VIII) | 63869 | (3S,5R)-5-{[tert-butyl(diphenyl)silyl]oxy}-3-methylhexanoic acid | C23H32O3Si | 详情 | 详情 | |
| (IX) | 63872 | (3S,5R)-5-{[tert-butyl(diphenyl)silyl]oxy}-3-methylhexanal | C23H32O2Si | 详情 | 详情 | |
| (X) | 63873 | (4S)-4-((2R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-2-methylpentyl)-2-oxetanone | C25H34O3Si | 详情 | 详情 | |
| (XI) | 63874 | C7H13LiN2 | 详情 | 详情 | ||
| (XII) | 63875 | (2R)-2-((2R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-2-methylpentyl)-2,3-dihydro-4H-pyran-4-one | C27H36O3Si | 详情 | 详情 | |
| (XIII) | 63879 | C27H37AcO3Si | 详情 | 详情 | ||
| (XIV) | 63878 | (2R,4S)-2-[(2R)-2-methyl-4-oxopentyl]-3,4-dihydro-2H-pyran-4-yl acetate | C13H20O4 | 详情 | 详情 | |
| (XV) | 63877 | tert-butyl 2-(tributylstannyl)-2,3-butadienoate | C20H38O2Sn | 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 |
合成路线2
该中间体在本合成路线中的序号：(XVI)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 |