A Proline and 4‐Hydroxyproline Based Approach to Enantiopure Pyrrolidin‐2‐yl‐Substituted Pyridine and Pyrimidine Derivatives

Abstract The optimized coupling of N‐protected ( S )‐proline and (2 S ,4 R )‐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 (2 S ,4 R )‐4‐hydroxyproline‐derived β‐ketoenamides to approach a library of novel chiral pool‐derived enantiopure functionalized pyridine and pyrimidine derivatives.