Production of High Value Amine Intermediates via Biocatalytic Cascades in Continuous Flow
2021
A key aim of biocatalysis is to mimic the
ability of eukaryotic cells to carry out compartmentalized multistep cascades
in a controlled and selective way. As biocatalytic cascades get longer and more
complex, reactions become unattainable under typical batch conditions. Here a
continuous flow multipoint injection reactor was combined with switching valves
to overcome batch incompatibility, thus allowing for successful biocatalytic
reaction cascades. As proof-of-principle, several reactive carbonyl intermediates
were generated in situ using galactose oxidase and engineered choline
oxidases, then passed directly to a series of packed-bed modules containing
different aminating biocatalysts which accordingly produced a range of
structurally distinct amines. The method was expanded to employ a batch
incompatible sequential amination cascade via
an oxidase-transaminase-imine reductase sequence, introducing different
amine reagents at each step without cross reactivity. The
combined approaches allowed for the biocatalytic synthesis of the natural
product alkaloid precursor 4O-methylnorbelladine. The
flow biocatalysis platform shown here significantly increases the scope of novel
biocatalytic cascades, removing previous limitations due to reaction and
reagent batch incompatibility.
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