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【结 构 式】 
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【分子编号】52845 【品名】(3R,4S,5S,6R)-4-[(E)-4-hydroxy-1-methyl-1-butenyl]-5-methoxy-1-oxaspiro[2.5]oct-6-yl benzoate 【CA登记号】 |
【 分 子 式 】C20H26O5 【 分 子 量 】346.42344 【元素组成】C 69.34% H 7.56% O 23.09% |
合成路线1
该中间体在本合成路线中的序号：(XVIII)Lithiation of dihydrofuran (VIII), followed by the addition of tributylstannyllithium, gave an intermediate (IX) that was quenched with methyl iodide to produce alcohol (X). Silylation of alcohol (X) with tert-butyl dimethylsilyl chloride then gave silyl ether (XI). Copper-catalyzed conjugate addition of the organolithium reagent derived from (XI) to the intermediate enone (VII), with subsequent enolate trapping with triethylsilyl chloride, afforded adduct (XII) as the major diastereoisomer. Epoxidation of the silyl enol ether (XII) with m-chloroperbenzoic acid, followed by selective desilylation using tetrabutylammonium fluoride/ammonium chloride, gave rise to hydroxy ketone (XIII). Methylation of (XIII) in the presence of silver oxide yielded methyl ether (XIV). Then, the keto group of (XIV) was stereoselectively reduced to (XV) employing L-selectride. After protection of the hydroxyl group of (XV) as the benzoate ester, simultaneous deprotection of the ketal and silyl ether functions under acidic conditions provided triol (XVI). Oxidative cleavage of the 1,2-diol moiety of (XVI) with NaIO4 gave ketone (XVII). This was converted to epoxide (XVIII) by stereoselective addition of in situ generated trimethylsulfoxonium ylide.
| 【1】 Taber, D.F.; et al.; Synthesis of (-)-fumagillin. J Am Chem Soc 1999, 121, 23, 5589. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 52835 | (5S)-2,2-dimethyl-1,3-dioxaspiro[4.5]dec-6-en-8-one | C10H14O3 | 详情 | 详情 | |
| (VIII) | 22766 | 2,3-dihydrofuran | 1191-99-7 | C4H6O | 详情 | 详情 |
| (IX) | 52836 | [(E)-4-oxido-1-(tributylstannyl)-1-butenyl]lithium | C16H32LiOSn | 详情 | 详情 | |
| (X) | 52837 | (E)-4-(tributylstannyl)-3-penten-1-ol | C17H36OSn | 详情 | 详情 | |
| (XI) | 52838 | tert-butyl(dimethyl){[(E)-4-(tributylstannyl)-3-pentenyl]oxy}silane; tert-butyl(dimethyl)silyl (E)-4-(tributylstannyl)-3-pentenyl ether | C23H50OSiSn | 详情 | 详情 | |
| (XII) | 52839 | tert-butyl(dimethyl)silyl (E)-4-{(5S,6R)-2,2-dimethyl-8-[(triethylsilyl)oxy]-1,3-dioxaspiro[4.5]dec-7-en-6-yl}-3-pentenyl ether; tert-butyl[((E)-4-{(5S,6R)-2,2-dimethyl-8-[(triethylsilyl)oxy]-1,3-dioxaspiro[4.5]dec-7-en-6-yl}-3-pentenyl)oxy]dimethylsilane | C27H52O4Si2 | 详情 | 详情 | |
| (XIII) | 52840 | (5S,6S,7S)-6-((E)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-1-butenyl)-7-hydroxy-2,2-dimethyl-1,3-dioxaspiro[4.5]decan-8-one | C21H38O5Si | 详情 | 详情 | |
| (XIV) | 52841 | (5S,6S,7S)-6-((E)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-1-butenyl)-7-methoxy-2,2-dimethyl-1,3-dioxaspiro[4.5]decan-8-one | C22H40O5Si | 详情 | 详情 | |
| (XV) | 52842 | (5S,6S,7S,8R)-6-((E)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-1-butenyl)-7-methoxy-2,2-dimethyl-1,3-dioxaspiro[4.5]decan-8-ol | C22H42O5Si | 详情 | 详情 | |
| (XVI) | 52843 | (1R,2S,3S,4S)-4-hydroxy-4-(hydroxymethyl)-3-[(E)-4-hydroxy-1-methyl-1-butenyl]-2-methoxycyclohexyl benzoate | C20H28O6 | 详情 | 详情 | |
| (XVII) | 52844 | (1R,2S,3S)-3-[(E)-4-hydroxy-1-methyl-1-butenyl]-2-methoxy-4-oxocyclohexyl benzoate | C19H24O5 | 详情 | 详情 | |
| (XVIII) | 52845 | (3R,4S,5S,6R)-4-[(E)-4-hydroxy-1-methyl-1-butenyl]-5-methoxy-1-oxaspiro[2.5]oct-6-yl benzoate | C20H26O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVIII)The second epoxide function was introduced into (XVIII) upon treatment with m-chloroperbenzoic acid, yielding (XIX). Oxidation of the primary alcohol of (XIX) to aldehyde (XX) was effected by means of Dess-Martin periodinane reagent. Subsequent Wittig reaction of aldehyde (XX) with isopropylidene triphenylphosphorane furnished olefin (XXI). The chiral fumagillol (-)-(XXII) was then obtained by hydrolysis of the benzoate ester (XXI) in the presence of methanolic K2CO3. Finally, condensation of alcohol (-)-(XXII) with the acid chloride (XXIII) led to the title compound.
| 【1】 Taber, D.F.; et al.; Synthesis of (-)-fumagillin. J Am Chem Soc 1999, 121, 23, 5589. |
| 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) | 52845 | (3R,4S,5S,6R)-4-[(E)-4-hydroxy-1-methyl-1-butenyl]-5-methoxy-1-oxaspiro[2.5]oct-6-yl benzoate | C20H26O5 | 详情 | 详情 | |
| (XIX) | 52846 | (3R,4S,5S,6R)-4-[(2R,3R)-3-(2-hydroxyethyl)-2-methyloxiranyl]-5-methoxy-1-oxaspiro[2.5]oct-6-yl benzoate | C20H26O6 | 详情 | 详情 | |
| (XX) | 52847 | (3R,4S,5S,6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(2-oxoethyl)oxiranyl]-1-oxaspiro[2.5]oct-6-yl benzoate | C20H24O6 | 详情 | 详情 | |
| (XXI) | 52848 | (3R,4S,5S,6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2.5]oct-6-yl benzoate | C23H30O5 | 详情 | 详情 | |
| (XXII) | 13712 | (3R,4S,5S,6R)-5-Methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2.5]octan-6-ol | C16H26O4 | 详情 | 详情 | |
| (XXIII) | 52849 | (2E,4E,6E,8E)-2,4,6,8-decatetraenedioyl dichloride | C10H8Cl2O2 | 详情 | 详情 |