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.
Highlights
Pyroglutamic acid and its derivatives are a valuable class of compounds, being found in various natural products and pharmaceuticals
The affinity with receptors has been modulated by changing substituents in the first, second, and fourth position of the lactam ring (Scheme 1) [4]
The preparation of enantiomerically pure 3-substituted pyroglutamic acid derivatives enables to explore the importance of substitution in the first and the third positions of lactam ring and their impact on biological activity
Summary
Pyroglutamic acid and its derivatives are a valuable class of compounds, being found in various natural products and pharmaceuticals It represents either an important chiral auxiliary or building block for the asymmetric synthesis of many biologically and pharmaceutically valuable compounds.[1] pyroglutamic acid derivatives have recently appeared to be efficient antagonists of specific types of purinergic receptors. Their inhibition has a promising impact on treating neurodegenerative diseases such as Alzheimer, Huntington, and Parkinson’s disease [2].
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