(S)-Pramipexole and Its Enantiomer, Dexpramipexole: A New Chemoenzymatic Synthesis and Crystallographic Investigation of Key Enantiomeric Intermediates

• Published in: Catalysts
• Main Authors: Samuele Ciceri, Patrizia Ferraboschi, Paride Grisenti, Shahrzad Reza Elahi, Carlo Castellano, Matteo Mori, Fiorella Meneghetti
• Format: Text
• Language: English
• Published: Multidisciplinary Digital Publishing Institute 2020
• Subjects: chiral synthons; pramipexole; dexpramipexole; Parkinson’s disease; hypereosinophilic syndromes; biocatalysis; asymmetric synthesis; Candida antarctica Lipase A; irreversible transesterification; crystal structures; Antarc*; Antarctica
• Online Access: https://doi.org/10.3390/catal10080941

A new chemoenzymatic method has been developed for the synthesis of (S)- and (R)-N-(6-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl) acetamide, two key synthons for the preparation of (S)-pramipexole, an anti-Parkinson drug, and its enantiomer dexpramipexole, which is currently under investigation for the treatment of eosinophil-associated disorders. These two building blocks have been obtained in good yields and high enantiomeric excess (30% and >98% ee for the R-enantiomer, and 31% and >99% ee for the S- one) through a careful optimization of the reaction conditions, starting from the corresponding racemic mixture and using two consecutive irreversible transesterifications, catalyzed by Candida antarctica lipase type A. Single crystal X-ray analysis has been carried out to unambiguously define the stereochemistry of the two enantiomers, and to explore in depth their three-dimensional features.