A Chiral Pool Strategy for the Synthesis of Enantiopure Hydroxymethyl-Substituted Pyridine Derivatives

作者：Eidamshaus Christian; Reissig Hans Ulrich^*

来源：European Journal of Organic Chemistry, 2011, 2011(30): 6056-6069.

DOI：10.1002/ejoc.201100681

• Enantiopure pyridines
• 4-Pyridones
• Cyclocondensation
• beta-Ketoenamides
• Nitrogen heterocycles
• Palladium catalysis
• Chiral pool

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.

• 出版日期2011-10