The optimized coupling of N-protected (S)-proline and (2S,4R)-4-hydroxyproline derivatives with (Z)-4-aminopent-3-en-2-one provided the expected β-ketoenamides in good to excellent yields. The subsequent intramolecular cyclizations afforded enantiopure pyridin-4-one derivatives with pyrrolidin-2-yl substituents. The nonaflates generated from these intermediates were excellent precursors for typical palladium-catalyzed coupling reactions. Oxidation with m-chloroperbenzoic acid gave pyrrolidine N-oxides whose subsequent reactions were investigated. The condensation of β-ketoenamides with hydroxylamine hydrochloride furnished the corresponding enantiopure pyrimidine N-oxides in good yields. The subsequent Boekelheide rearrangement provided hydroxymethyl-substituted pyrimidine derivatives together with minor components. Overall, this study nicely demonstrates the potential of (S)-proline- or (2S,4R)-4-hydroxyproline-derived β-ketoenamides to approach a library of novel chiral pool-derived enantiopure functionalized pyridine and pyrimidine derivatives.
