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手性醇的合成—— Sharpless 不对称双羟化及不对称羟胺化2020-07-31

1、 Sharpless 不对称双羟化 

      由于四氧化锇或者高锰酸钾都可以从烯烃的平面的任意一侧与烯烃形成环状酯,所以得到的顺式羟基化产物必为两种对映体的混合物,这两种氧化剂都没有高对映选择性,所以发现和寻求具有高对映选择性的氧化催化剂,是研究者追求的目标。这样的探索始于 20 世纪初,直到 20 世纪 90 年代初才获得较好的结果。这一领域的先锋是 Sharpless 小组,他们和其他小组一样主要在寻找有效的四氧化锇与手性配体的配合物。并且认为 受性配体是手性生物碱配体与四氧化锇结合得越牢,越稳定,则产物的%ee 值就越高。发现这一类型手性配体的轨迹始于手性吡啶与四氧化锇所形成配合物,用此作为催化 剂,所得到的邻二醇仅有很低的对应体纯度(3%-18% ee),原因在于四氧化锇和手性吡 啶配和物不稳定。但是这是一个很好的提示,Sharpless 等人选择天然的金鸡纳生物碱,即奎宁和奎尼定(衍生为二氢奎宁和二氢奎尼定酯类)作手性配体,结果四氧化锇与奎 宁环上的桥头手性氮原子有很强的结合,使邻二醇有了教高的对映体过量(可达到>80% ee),而且将反应的速度提高了 1-2 数量级。

 Sharpless 不对称双羟化示例 

   A mixture of 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[trans-(2-buten-1-yl)oxy] quinazoline (1.30 g), a solution of osmium tetroxide in t-butanol (osmium tetroxide 106 mg/t-butanol 8.36 g) (312 mg) and 4-methylmorpholine N-oxide (382 mg) acetone is distilled off from the reaction mixture under reduced pressure, and the resultant product is diluted with ethyl acetate, and the mixture is washed with 10percent aqueous sodium sulfite solution and water. in water (2 ml)–acetone (15 ml) is stirred at room temperature for 14 hours.. The ethyl acetate solution is dried over anhydrous magnesium sulfate and evaporated to dryness under  reduced pressure, and the residue is purified by medium pressure liquid column chromatography (eluent, chloroform:methanol=100:1,v/v)to give 2-[4-(benzyloxycarbonyl)piperazin-1-yl]

2、Sharpless 不对称羟胺化        

      在很多的生物学上很重要的分子中,立体 β-胺基醇结构单元是关键的部分。要合成这样 的分子或其衍生物,烯烃与这两种杂原子直接加成为直接的方法。虽然 20 多年前就已经知道的锇或钯参与的烯烃氨基羟基化反应,但是为了将这一反应发展成为催化性的不对称过程,仍存在一些问题。小组近发现的锇参与的不对称氨基羟基化反应(AA 反应),可以优异的对映选择性和极好的产率直接将这种官能团引入烯烃。 

1、Sharpless 不对称羟胺化示例 

    A 20 ml of scintillation vial equipped with a magnetic stirrer was charged with a solution of MeSO2NclNa(455mg, 3.0mmol, 3.0 equiv) in 7.5 ml of water, 7.5 ml of nPrOH, and (DHQD)2PHAL (40mg, 0.05mmol, 0.05 equiv). To the resulting stirred clear colorless solution was then added isopropyl trans-cinnmate (190mg, 1.0mmol), followed by K2Os2(OH)4(14.8mg, 0.04mmol, 0.04 equiv). The reaction mixture turned green after several minutes and was stirred for 3.5 hours, by which time the reaction mixture has turned a clear, light yellow. The presumed significance of the color change as an indication of the end point of the reaction was confirmed by a TLC analysis, which revealed that no olefin remained. (With dimethyl fumarate the green color was only observed when an additional 0.5 equiv tert-butyl hypochlorite was added. For the fumarate case, the extra tert-butyl hypochlorite also resulted in much better ee and yield.) the reaction was then quenched by addition of 10 ml of saturated Na2S3( This reductive quench is exothermic and cooling is needed for large-scales). The added salt caused phase separation. The aqueous phase was separated and extracted with ethyl acetate(3X30ml). The combined organic phases were dried over Mg2SO4 and concentrated to afford the crude product(impurities were mainly methanesulfonamide and diol). For an accurate yield the crude product was purified by flash chromatography( SiO2, 30% ethyl acetate/hexane) and afforded 195mg(65%, >99%ee) crystalline aminohydroxylation product. 

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