The integration of biocatalytic transformations into the synthesis of commercial fine chemical and pharmaceutical products is becoming increasingly widespread, with attendant environmental and economic benefits. The unparalleled specificity that biocatalysis provides can be exploited by synthetic chemists to build molecular complexity. Despite emerging as one of the most promising technologies to enable “green” synthesis of important chemicals, biocatalysis has been hindered by the high cost associated with recombinant proteins.
Due to the inherent advantages of continuous flow, the synergy between biocatalysis and continuous flow has the capability to increase the efficacy of many biocatalytic reactions. However, for continuous flow biocatalysis to be efficient, it is paramount the enzyme is retained within the reactor. This can be realised through either the separation and recycling of soluble enzyme or through immobilisation.
Immobilisation of enzymes increases their thermal and pH stability as well as facilitating the recyclability of the enzyme. Furthermore, immobilisation can also allow for easier work-up and purification of the product, which underpins why immobilisation is now fundamental for the economic and commercial utilization of enzymes. Despite these advantages, immobilisation isn’t exempt from limitations, with a loss of activity and selectivity, as well as increased costs amongst some of the common problems associated with immobilisation.
Current use of biocatalysts within continuous flow is limited by several factors. These include the variable performance of the immobilisation supports and the mismatching of these supports to the type of reactor (tubular, CSTR). In addition, many examples of continuous flow biocatalysis have been limited to cofactor independent enzymes, in part, due to inefficient cofactor recycling/regeneration systems.
Whilst there have been numerous reported examples of chemo- and bio-catalysis in continuous flow, the complexity of combining these processes in one system is highlighted by the limited amount of reported literature in this field. This is mainly due to the divergent reaction conditions that each system requires.
The core technological challenges associated with continuous flow chemoenzymatic cascades, namely the divergent reaction conditions and cofactor recycling, may be overcome with a combination of enzyme immobilisation, reaction compartmentalization and continuous separations. If these technologies can be successfully combined, this suggests that the resultant expansion within the field would enable new synthetic routes to key chiral intermediates of bio-active structures, with positive impacts on the efficiency and sustainability of the process.
- MChem (with Industry) from the University of York