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

• Main Authors: Samuele Ciceri, Patrizia Ferraboschi, Paride Grisenti, Shahrzad Reza Elahi, Carlo Castellano, Matteo Mori, Fiorella Meneghetti
• Format: Article
• Language: English
• Published: MDPI AG 2020-08-01
• Series: Catalysts
• Subjects: chiral synthons; pramipexole; dexpramipexole; Parkinson’s disease; hypereosinophilic syndromes; biocatalysis
• Online Access: https://www.mdpi.com/2073-4344/10/8/941

A new chemoenzymatic method has been developed for the synthesis of (<i>S</i>)- and (<i>R</i>)-<i>N</i>-(6-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl) acetamide, two key synthons for the preparation of (<i>S</i>)-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 <i>R</i>-enantiomer, and 31% and >99% ee for the <i>S</i>- one) through a careful optimization of the reaction conditions, starting from the corresponding racemic mixture and using two consecutive irreversible transesterifications, catalyzed by <i>Candida antarctica</i> 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.