A Chiral Pool Strategy for the Synthesis of Enantiopure Hydroxymethyl-Substituted Pyridine Derivatives
A Chiral Pool Strategy for the Synthesis of Enantiopure Hydroxymethyl-Substituted Pyridine Derivatives
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DOI：
10.1002/ejoc.201100681
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发表时间：
2011-10-01
影响因子：
2.8
通讯作者：
Reissig, Hans-Ulrich
中科院分区：
文献类型：
--
作者：
Eidamshaus, Christian;Reissig, Hans-Ulrich
介绍了一种合成对映体纯的羟甲基取代吡啶衍生物的简便方法。所开发的方法是基于TMSOTf促进的β-酮酰胺的环缩合，导致不同取代的4-羟基吡啶/4-吡啶酮衍生物。所需的β-酮烯酰胺是通过容易获得的烯氨基酮与适当保护的对映体纯的羧氯化物的酰化反应制备的。大多数实验是以D-扁桃酸为起始原料进行的。已经表明，所有步骤基本上在没有外消旋化的情况下发生。将几种制备的4-吡啶酮衍生物转化为相应的吡啶-4-基壬氟磺酸酯，并进行一系列钯催化的转化，如Suzuki，Heck或Sonogashira反应。此外，区域选择性侧链官能化的不对称的2，6-二取代的吡啶衍生物的Boekelheide重排的相应的吡啶N-氧化物的应用程序完成。所提出的方法允许一种灵活、快速和可扩展的方法来制备高度取代的对映体纯的吡啶衍生物。
A simple procedure for the synthesis of enantiopure hydroxymethyl-substituted pyridine derivatives is presented. The developed method is based on TMSOTf-promoted cyclocondensations of beta-ketoenamides, leading to differently substituted 4-hydroxypyridine/4-pyridone derivatives. The required beta-ketoenamides were prepared by acylation of easily available enamino ketones with suitably protected enantiopure carboxylic chlorides. Most of the experiments were performed with D-mandelic acid as starting material. It has been shown that all steps occur essentially without racemisation. Several of the prepared 4-pyridone derivatives were transformed into the corresponding pyrid-4-yl nonaflates and subjected to a series of palladium-catalysed transformations, such as Suzuki, Heck or Sonogashira reactions. In addition, regioselective side-chain functionalisation of unsymmetrically 2,6-disubstituted pyridine derivatives was accomplished by application of Boekelheide rearrangements of the corresponding pyridine N-oxides. The presented methods allow a flexible, rapid and scalable approach to highly substituted, enantiopure pyridine derivatives.