Enzymatic and Chemoenzymatic Cascades for the Preparation of Chiral Amines

  • Jack Sangster

Student thesis: Phd

Abstract

The amine moiety is contained in a wide variety of naturally occurring molecules including proteins, DNA and alkaloids.1 It is unsurprising then, that amine containing pharmaceuticals make up approximately 40% of new chemical entities (NTEs).2 The continued interest of pharmaceutical companies in the chiral amine functional group has spearheaded the development of novel catalytic methodologies to access these targets. However, these catalytic methods are often inefficient, requiring rare metal catalysts and ligands making the process unsustainable.3–5 This has stimulated the development of enzyme catalysed approaches for the synthesis of chiral amines.6–8 These enzymes mediated transformations are highly chemo-, regio- and stereo-selective and occur in environmentally benign conditions, but these enzymatic approaches can be limited by the number of currently discovered enzymes.9 It is possible to overcome this caveat by combining both chemo- and bio-catalytic approaches, so called chemoenzymatic catalysis, to access a much larger region of chemical space.10 Over the last decade the Turner group has exploited imine reductases (IREDs) for the preparation of chiral amines.11–14 IREDs have been shown to catalyse the reduction of preformed cyclic imines, and where the imine substrate is prochiral, it is reduced asymmetrically with high enantiomeric excess. However, these enzymes have not been shown to catalyse an enantioselective C-C bond formation alpha to a nitrogen. The work that is outlined in the rest of this thesis is focussed on developing enzymatic cascades involving asymmetric C-C bond formation for the preparation of chiral amines. This thesis aims to address the modest collection of enzymatic methods to catalyse C-C bond formation through combining chemo- and biocatalysis, towards the preparation of chiral amines.
Date of Award1 Aug 2023
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorSabine Flitsch (Supervisor) & Nicholas Turner (Supervisor)

Keywords

  • Enantioselectivity
  • C-C Bond Formation
  • Biocatalysis
  • Chemistry

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