(497g) Dynamic Resolution for Separation-Free Enantiomeric Purification in Flow

Authors: 
Weeranoppanant, N., Massachusetts Institute of Technology
Jensen, K. F., Massachusetts Institute of Technology
Shahane, S., Massachusetts Institute of Technology
Chiral separations of biologically active small molecules is a critical process in the synthetic pathways for pharmaceutics. Commercial processes often necessitate the use of large batch crystalizers or slow, solvent intensive chromatographic columns. In recent years, dynamic resolution of chiral compounds have demonstrated great promise in providing chemical pathways for driving racemic mixtures to single component chiral species. Typical pathways utilize a batch slurry reactor that contains two catalysts which perform the series reactions: enantioselective irreversible transesterification (enzyme) and racemization (precious metal). Such methodologies, however, are greatly limited in application by requiring the series reactions to operate homogenously and under identical reaction conditions. The heavy metals are then required to be separated downstream and the spent catalysts are discarded.

In this work, we introduce a chemical synthesis for the successful immobilization of a ruthenium metal complex for the efficient racemization of chiral molecules. The ligand-supported complex performs the series oxidation-reduction over several substrates in a model alcohol system. Additionally, the successful immobilization has enabled the introduction of a continuous flow-based technique whereby two micro-packed beds are charged in series with the immobilized enzyme and racemization catalysts. The use of a recycle system and in-line gas stripping allows for nearly quantitative enantiomeric selectivity.