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Production of High Value Amine Intermediates via Biocatalytic Cascades in Continuous Flow

Baldwin, C; Thompson, MP; Turner, N; Pamer, R; Ford, G; Citoler, J; Mattey, AP; Marshall, J; Flitsch, S; Cosgrove, S


C Baldwin

MP Thompson

N Turner

R Pamer

G Ford

J Citoler

AP Mattey

J Marshall

S Flitsch


<jats:p>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 <jats:italic>in situ </jats:italic>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 <jats:italic>via </jats:italic>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.</jats:p>

Acceptance Date Feb 17, 2021
Online Publication Date Feb 17, 2021
Publication Date Feb 17, 2021
Journal Organic Chemistry
Print ISSN 2573-2293
Publisher Cambridge University Press
Peer Reviewed Not Peer Reviewed
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