Optimising continuous flow chemoenzymatic processes for fine chemical manufacturing Harrison Johnson-Evans 1,2 ; John Blacker 1,2 ; Nikil Kapur 2,3 , Mark Dow 4 ; Mark Muldowney 5 ; Greg Holgate 5 ; Steve Marsden 1,2 1 School of Chemistry, University of Leeds, 2 Institute of Process Research and Development, University of Leeds, 3 School of Mechanical Engineering, University of Leeds, 4 Chemical Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Macclesfield, UK, 5 Sterling Pharma Solutions, UK The advancement in enzyme engineering has led to the integration of biocatalytic transformations into the synthesis of commercial fine chemical and pharmaceutical products becoming increasingly widespread.(1,2) With continuous flow facilitating multi-step cascade synthesis, the synergy of bio- and chemo-catalysis can be realised in order to access complex molecules including active pharmaceutical ingredients (APIs). Whilst the combination of bio- and chemo-catalysis within a continuous flow system opens new synthetic avenues, the limited number of examples reported in the literature (3,4) highlights the challenges within this field. The core technological challenges associated with synergistic bio- and chemo-catalysis, namely the divergent reaction conditions and cofactor recycling, may be overcome with a combination of enzyme immobilisation, reaction compartmentalization and continuous separations. Utilisation of enzymes, in combination with highly atom efficient chemocatalytic methodologies, not only enables access to enantiomerically enriched secondary amines, but does so in a ‘green’ manner. Consequently, new synthetic routes to complex chiral molecules through chemoenzymatic cascades will become more readily available. The focus of this work is the enhancement of chemoenzymatic cascades in continuous flow, fusing enzyme immobilisation, reaction compartmentalisation and ‘clean’ N-alkylation methodologies, for the synthesis of pharmaceutically relevant chiral amines (Figure 1).
Figure 1: Four alternative routes to enantiomerically enriched secondary amines via chemoenzymatic continuous flow cascades. Two alternative enzymes, transaminase and lipase, can be used to access the same primary amine intermediate, while two chemocatalytic processes can be used to access pharmaceutically-relevant secondary amines. References 1. T. Sugai, S. Higashibayashi and K. Hanaya, Tetrahedron, 2018, 74, 3469-3487. 2. G. Hughes and J. C. Lewis, Chem. Rev., 2018, 118, 1-3.
3. J. H. Schrittwieser, S. Velikogne, M. Hall and W. Kroutil, Chem. Rev., 2018, 118, 270-348. 4. A. D. Clayton, R. Labes and A. J. Blacker, Curr. Opin. Green Sustain., 2020, 26, 100378.
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