Formation of Dihydropyridone- and Pyridone-Based Peptide Analogs through Aza-Annulation of β-Enamino Ester and Amide Substrates with α-Amido Acrylate Derivatives

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Abstract

The aza-annulation of β-enamino ester and amide substrates with the mixed anhydride of 2-acetamidoacrylic acid was used for the efficient construction of highly substituted α-acetamido δ-lactam products. With the α-acetamido substituent, lactam functionality, and γ-carboxylate group, these δ-lactam products represent an interesting class of conformationally restricted dipeptide analogs. The framework of this lactam hub is structurally related to that of an α-amino acid coupled with a β-amino acid. When α-amino esters derived from naturally occurring amino acids were used in the enamine formation step, subsequent aza-annulation led to branched peptide surrogates with two C-termini that extended from a common N-terminus. Oxidation of the aza-annulation products resulted in the generation of a planar system with peptide functionality radiating from the 1, 3, and 5 positions of the pyridone hub. Alternatively, pyridone products could be formed directly from the enamino amides by reaction with 2-phenyl-4-(ethoxymethylene)oxazolone. Subsequent hydrolysis of the acetamido and ester substituents of the N-benzylpyridones was selectively performed to access unique β-amino acid products. Formation of the mixed anhydride of this acid, followed by amide bond formation with the ester of an α-amino acid, allowed extension of the peptide chain from the dihydropyridone structure.

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