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【结 构 式】 
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【分子编号】62136 【品名】(2R,3R,5S,6S)-6-((2E,4E)-5-{(3R,4R,5R,7R)-7-(iodomethyl)-4-[(triethylsilyl)oxy]-1,6-dioxaspiro[2.5]oct-5-yl}-3-methyl-2,4-pentadienyl)-2,5-dimethyltetrahydro-2H-pyran-3-amine; (2R,3R,5S,6S)-6-((2E,4E)-5-{(3R,4R,5R,7R)-7-(iodomethyl)-4-[(triethylsilyl)oxy]-1,6-dioxaspiro[2.5]oct-5-yl}-3-methyl-2,4-pentadienyl)-2,5-dimethyltetrahydro-2H-pyran-3-ylamine 【CA登记号】 |
【 分 子 式 】C26H46INO4Si 【 分 子 量 】591.64555 【元素组成】C 52.78% H 7.84% I 21.45% N 2.37% O 10.82% Si 4.75% |
合成路线1
该中间体在本合成路线中的序号：(XXIX)Enantioselective cycloaddition of dienyne (XVII) with aldehyde (XVIII) affords dihydropyran (XIX). Subsequent Rubottom oxidation of the silyl enol ether (XIX) gives a mixture of epimeric alpha-hydroxy ketones (XX), which is further equilibrated to the desired stereoisomer (XXI) in the presence of K2CO3 in MeOH. After protection of the hydroxyl group of (XXI) as the triisopropylsilyl ether (XXII), Wittig reaction with methylene triphenylphosphorane provides the exocyclic olefin (XXIII). Replacement of the silylated primary hydroxyl of (XXIII) with a iodide group to yield (XXIV) is accomplished by treatment with I2 and PPh3. Removal of the remaining silyl group of (XXIV) with tetrabutylammonium fluoride and acetic acid yields the allylic alcohol (XXV), which can be diastereoselectively epoxidized with t butyl hydroperoxide and vanadyl acetylacetonate, producing (XXVI) as a single isomer. Reprotection of (XXVI) with triisopropylsilyl triflate affords the corresponding silyl ether (XXVII). Hydrozirconation of acetylene (XXVII), followed by Negishi coupling with the vinyl iodide (XVI) furnishes the diene system (XXVIII). Subsequent azido group reduction in (XXVIII) with trimethylphosphine in moist THF provides amine (XXIX).
| 【1】 Thompson, C.F.; Jamison, T.F; Jacobsen, E.N.; Total synthesis of FR901464. Convergent assembly of chiral componenents prepared by asymmetric catalysis. J Am Chem Soc 2000, 122, 45, 10482. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVI) | 62124 | (2R,3R,5S,6S)-6-[(E)-3-iodo-2-butenyl]-2,5-dimethyltetrahydro-2H-pyran-3-yl azide; (2R,3R,5S,6S)-3-azido-6-[(E)-3-iodo-2-butenyl]-2,5-dimethyltetrahydro-2H-pyran | C11H18IN3O | 详情 | 详情 | |
| (XVII) | 62125 | triethyl{[(E)-1-methylene-2-penten-4-ynyl]oxy}silane; (E)-1-methylene-2-penten-4-ynyl triethylsilyl ether | C12H20OSi | 详情 | 详情 | |
| (XVIII) | 61170 | 2-{[tert-butyl(dimethyl)silyl]oxy}acetaldehyde；tert-butyldimethylsilyloxy acetaldehyde | 102191-92-4 | C8H18O2Si | 详情 | 详情 |
| (XIX) | 62126 | tert-butyl(dimethyl)silyl {(2R,6S)-6-ethynyl-4-[(triethylsilyl)oxy]-3,6-dihydro-2H-pyran-2-yl}methyl ether; tert-butyl({(2R,6S)-6-ethynyl-4-[(triethylsilyl)oxy]-3,6-dihydro-2H-pyran-2-yl}methoxy)dimethylsilane | C20H38O3Si2 | 详情 | 详情 | |
| (XX) | 62127 | (2R,6R)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-ethynyl-3-hydroxytetrahydro-4H-pyran-4-one | C14H24O4Si | 详情 | 详情 | |
| (XXI) | 62128 | (2R,3R,6R)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-ethynyl-3-hydroxytetrahydro-4H-pyran-4-one | C14H24O4Si | 详情 | 详情 | |
| (XXII) | 62129 | (2R,3R,6R)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-ethynyl-3-[(triisopropylsilyl)oxy]tetrahydro-4H-pyran-4-one | C23H44O4Si2 | 详情 | 详情 | |
| (XXIII) | 62130 | tert-butyl(dimethyl)silyl {(2R,5S,6R)-6-ethynyl-4-methylene-5-[(triisopropylsilyl)oxy]tetrahydro-2H-pyran-2-yl}methyl ether; tert-butyl({(2R,5S,6R)-6-ethynyl-4-methylene-5-[(triisopropylsilyl)oxy]tetrahydro-2H-pyran-2-yl}methoxy)dimethylsilane | C24H46O3Si2 | 详情 | 详情 | |
| (XXIV) | 62131 | (2R,3S,6R)-2-ethynyl-6-(iodomethyl)-4-methylenetetrahydro-2H-pyran-3-yl triisopropylsilyl ether; {[(2R,3S,6R)-2-ethynyl-6-(iodomethyl)-4-methylenetetrahydro-2H-pyran-3-yl]oxy}(triisopropyl)silane | C18H31IO2Si | 详情 | 详情 | |
| (XXV) | 62132 | (2R,3S,6R)-2-ethynyl-6-(iodomethyl)-4-methylenetetrahydro-2H-pyran-3-ol | C9H11IO2 | 详情 | 详情 | |
| (XXVI) | 62133 | (3R,4R,5R,7R)-5-ethynyl-7-(iodomethyl)-1,6-dioxaspiro[2.5]octan-4-ol | C9H11IO3 | 详情 | 详情 | |
| (XXVII) | 62134 | (3R,4R,5R,7R)-5-ethynyl-7-(iodomethyl)-1,6-dioxaspiro[2.5]oct-4-yl triethylsilyl ether; triethyl{[(3R,4R,5R,7R)-5-ethynyl-7-(iodomethyl)-1,6-dioxaspiro[2.5]oct-4-yl]oxy}silane | C15H25IO3Si | 详情 | 详情 | |
| (XXVIII) | 62135 | (3R,4R,5R,7R)-5-{(1E,3E)-5-[(2S,3S,5R,6R)-5-azido-3,6-dimethyltetrahydro-2H-pyran-2-yl]-3-methyl-1,3-pentadienyl}-7-(iodomethyl)-1,6-dioxaspiro[2.5]oct-4-yl triethylsilyl ether; {[(3R,4R,5R,7R)-5-{(1E,3E)-5-[(2S,3S,5R,6R)-5-azido-3,6-dimethyltetrahydro-2H-pyran-2-yl]-3-methyl-1,3-pentadienyl}-7-(iodomethyl)-1,6-dioxaspiro[2.5]oct-4-yl]oxy}(triethyl)silane | C26H44IN3O4Si | 详情 | 详情 | |
| (XXIX) | 62136 | (2R,3R,5S,6S)-6-((2E,4E)-5-{(3R,4R,5R,7R)-7-(iodomethyl)-4-[(triethylsilyl)oxy]-1,6-dioxaspiro[2.5]oct-5-yl}-3-methyl-2,4-pentadienyl)-2,5-dimethyltetrahydro-2H-pyran-3-amine; (2R,3R,5S,6S)-6-((2E,4E)-5-{(3R,4R,5R,7R)-7-(iodomethyl)-4-[(triethylsilyl)oxy]-1,6-dioxaspiro[2.5]oct-5-yl}-3-methyl-2,4-pentadienyl)-2,5-dimethyltetrahydro-2H-pyran-3-ylamine | C26H46INO4Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXIX)Acylation of amine (XXIX) with the unsaturated acid (V) in the presence of HBTU gives amide (XXX). Dehydroiodination of (XXX) by means of DBU in DMF leads to the exocyclic enol ether (XXXI). The O-silyl group of (XXXI) is then removed with tetrabutylammonium fluoride and acetic acid, to yield alcohol (XXXII). Finally, acid-catalyzed hydration of the cyclic enol ether (XXXII) in aqueous THF gives rise to the target hemiketal compound.
| 【1】 Thompson, C.F.; Jamison, T.F; Jacobsen, E.N.; Total synthesis of FR901464. Convergent assembly of chiral componenents prepared by asymmetric catalysis. J Am Chem Soc 2000, 122, 45, 10482. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 62113 | (Z,4S)-4-(acetyloxy)-2-pentenoic acid | C7H10O4 | 详情 | 详情 | |
| (XXIX) | 62136 | (2R,3R,5S,6S)-6-((2E,4E)-5-{(3R,4R,5R,7R)-7-(iodomethyl)-4-[(triethylsilyl)oxy]-1,6-dioxaspiro[2.5]oct-5-yl}-3-methyl-2,4-pentadienyl)-2,5-dimethyltetrahydro-2H-pyran-3-amine; (2R,3R,5S,6S)-6-((2E,4E)-5-{(3R,4R,5R,7R)-7-(iodomethyl)-4-[(triethylsilyl)oxy]-1,6-dioxaspiro[2.5]oct-5-yl}-3-methyl-2,4-pentadienyl)-2,5-dimethyltetrahydro-2H-pyran-3-ylamine | C26H46INO4Si | 详情 | 详情 | |
| (XXX) | 62137 | (1S,2Z)-4-{[(2R,3R,5S,6S)-6-((2E,4E)-5-{(3R,4R,5R,7R)-7-(iodomethyl)-4-[(triethylsilyl)oxy]-1,6-dioxaspiro[2.5]oct-5-yl}-3-methyl-2,4-pentadienyl)-2,5-dimethyltetrahydro-2H-pyran-3-yl]amino}-1-methyl-4-oxo-2-butenyl acetate | C33H54INO7Si | 详情 | 详情 | |
| (XXXI) | 62138 | (1S,2Z)-4-{[(2R,3R,5S,6S)-2,5-dimethyl-6-((2E,4E)-3-methyl-5-{(3R,4R,5R)-7-methylene-4-[(triethylsilyl)oxy]-1,6-dioxaspiro[2.5]oct-5-yl}-2,4-pentadienyl)tetrahydro-2H-pyran-3-yl]amino}-1-methyl-4-oxo-2-butenyl acetate | C33H53NO7Si | 详情 | 详情 | |
| (XXXII) | 62139 | (1S,2Z)-4-[((2R,3R,5S,6S)-6-{(2E,4E)-5-[(3R,4R,5R)-4-hydroxy-7-methylene-1,6-dioxaspiro[2.5]oct-5-yl]-3-methyl-2,4-pentadienyl}-2,5-dimethyltetrahydro-2H-pyran-3-yl)amino]-1-methyl-4-oxo-2-butenyl acetate | C27H39NO7 | 详情 | 详情 |