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

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.