1352002-28-8Relevant academic research and scientific papers
A chiral pool strategy for the synthesis of enantiopure hydroxymethyl-substituted pyridine derivatives
Eidamshaus, Christian,Reissig, Hans-Ulrich
, p. 6056 - 6069 (2011/12/15)
A simple procedure for the synthesis of enantiopure hydroxymethyl- substituted pyridine derivatives is presented. The developed method is based on TMSOTf-promoted cyclocondensations of β-ketoenamides, leading to differently substituted 4-hydroxypyridine/4-pyridone derivatives. The required β-ketoenamides were prepared by acylation ofeasily 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. A new route to hydroxymethyl-substituted pyridine derivatives, starting from enantiopure α-hydroxy carboxylic acids, is described. The synthetic value of the method is demonstrated by multifaceted functionalisation reactions of the prepared pyridine derivatives, leading to a series of highly substituted enantiopure pyridine derivatives.
