An investigation of the Chemoenzymatic Dynamic Kinetic Resolution of racemic amines is reported using a dual transition metal-enzyme catalysed process, as a methodology for the synthesis of chiral amines. This work is comprised of 4 sections: a literature review of the existing synthetic methodologies for the synthesis of chiral amines; the discovery and development of a Flash Thermal Racemisation (FTR) procedure; the interrogation of enzymatic kinetic resolution in continuous flow; and finally, implementation and analysis of the first demonstration of a compartmentalised FTR-CE-DKR under flow conditions.
Previously, Chemoenzymatic Dynamic Kinetic Resolution has been reported to be an effective approach for the resolution of chiral amines but was greatly limited by its inability to be conducted on an industrially relevant scale. The key challenge faced by the process is the lack of compatibility of the two tandem catalysts required for the racemisation and enzyme-catalysed acylation steps. Despite much effort, this process has been plagued by the compromises made, which have led to the use of sub-optimal reaction conditions for each individual step. Deactivation of the transition metal or enzyme catalysts has also been a problem leading to overall limited productivity and lack of scalability, rendering the processes of limited application in a commercial setting.
The development of the FTR-CE-DKR methodology reported here has demonstrated how continuous flow can be applied to effectively compartmentalise each step of the processes, thus allowing optimal conditions to be applied to each step. This has enabled proof-of-concept studies to be carried out that demonstrate the ability of this approach to greatly increase the productivity of the process to synthesise chiral amines in a scalable manner.