Synthesis of (2S,3S)-3-Aroyl Pyroglutamic Acid Amides

Abstract

A new methodology for the asymmetric synthesis of enantiomerically enriched 3-aroyl pyroglutamic acid derivatives has been developed through effective 5-exo-tet cyclization of N-chloroacetyl aroylalanines. The three-step sequence starts with the synthesis of N-substituted (S,S)-2-amino-4-aryl-4-oxobutanoic acids via highly diastereoselective tandem aza-Michael addition and crystallization-induced diastereomer transformation (CIDT). Their N-chloroacetylation followed by base-catalyzed cyclization and ultimate acid-catalyzed removal of chiral auxiliary without loss of stereochemical integrity furnishes the target substituted pyroglutamic acids. Finally, several series of their benzyl amides were prepared as 3-aroyl analogs of known P2X7 antagonists.