Pyrrolidine-2,4-diones (1, also known as tetramic acids) are naturally occurring compounds with a structure closely related to α-amino acids. In nature N-acylated pyrrolidine-2,4-diones exist as their 4-O-methyl ethers. The formation of the imide bond in these N-acylated pyrrolidinones has been difficult due to the tendency of the pyrrolin anion to racemize under basic conditions.

Our work comprises a facile synthesis of N-acylated O-alkylated pyrrolin-2-ones (2) in high yield and excellent enantiopurity. The method is compatible with both Fmoc-AA-OPfp and Boc-AA-ONp esters, thereby enabling further synthetic transformations. Molecular mechanics calculations suggest that the resulting dipeptide analogs adopt a linear, extended conformation.