Development of continuous flow systems to access secondary amines through previously incompatible biocatalytic cascades.

Mattey, Ashley P.; Ford, Grayson J.; Citoler, Joan; Baldwin, Christopher; Marshall, James R.; Palmer, Ryan B.; Thompson, Matthew; Turner, Nicholas J.; Cosgrove, Sebastian C.; Flitsch, Sabine L.

doi:10.1002/anie.202103805

Development of continuous flow systems to access secondary amines through previously incompatible biocatalytic cascades.

Mattey, Ashley P.; Ford, Grayson J.; Citoler, Joan; Baldwin, Christopher; Marshall, James R.; Palmer, Ryan B.; Thompson, Matthew; Turner, Nicholas J.; Cosgrove, Sebastian C.; Flitsch, Sabine L.

Authors

Ashley P. Mattey

Grayson J. Ford

Joan Citoler

Christopher Baldwin

James R. Marshall

Ryan B. Palmer

Matthew Thompson

Nicholas J. Turner

Sebastian Cosgrove s.cosgrove@keele.ac.uk

Sabine L. Flitsch

Abstract

A key aim of biocatalysis is to mimic the ability of eukaryotic cells to carry out multistep cascades in a controlled and selective way. As biocatalytic cascades get more complex, reactions become unattainable under typical batch conditions. Here a number of continuous flow systems were used to overcome batch incompatibility, thus allowing for successful biocatalytic cascades. As proof-of-principle, reactive carbonyl intermediates were generated in situ using alcohol 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 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.

Journal Article Type	Article
Acceptance Date	Apr 15, 2021
Online Publication Date	May 19, 2021
Publication Date	Aug 16, 2021
Publicly Available Date	Jun 26, 2023
Journal	Angewandte Chemie International Edition
Print ISSN	1433-7851
Publisher	Wiley
Peer Reviewed	Peer Reviewed
Volume	60
Issue	34
Pages	18660-18665
DOI	https://doi.org/10.1002/anie.202103805
Keywords	General Chemistry, Catalysis
Publisher URL	https://onlinelibrary.wiley.com/doi/10.1002/anie.202103805