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Enzymatic multi-step reactions offer significant potential to yield industrially relevant chiral intermediates and building blocks with excellent stereoselectivities. Still, the access to economically feasible product concentrations can be a challenge. By using an integrated engineering approach, encompassing enzyme engineering, reaction optimisation and optimal process design, this challenge can be adressed. This presentation focuses on the development of synthetic enzyme cascades for the production of pharmaceutically active ingredients meeting not only requirements on high selectivities (>98 %) therewith reducing waste, but also reaching product concentrations >50 g/l.
By the flexible combination of enzymes with varying substrate preferences or stereoselectivities, the access to product platforms is possible. E.g. starting from easily available aldehydes or keto acids, chiral amino alcohols can be synthesised by a combination of an enzymatically catalysed carboligation and a transamination step. Depending on the substitution pattern of the starting material, products like nor(pseudo)ephedrine, methoxamine or metaraminol are accessible. By the combination of (R)- and (S)-selective catalysts in a modular way, in most cases all four stereoisomers of the respective amino alcohol can be gained. Recently, 1-amino-1-phenylpropan-2-ol wascatalysed in a repetitive batch mode using immobilised catalysts to enhanced specific space-time-yields while cutting on catalyst costs.
On top, tetrahydroisoquinolines (THIQ) containing three chiral centres can be synthesised by
the addition of a cyclisation step. This step can be either catalysed by a norcoclaurine
synthase or by phosphate giving stereocomplementary products.
To further increase ecologic and economic efficiency, we investigate the potential in running multi-step biocatalysis in (environmentally benign) organic solvents or neat substrate systems. Whole cell biotransformations in micro-aqueous reaction systems do not only allow addition of poorly water-soluble substrates in high concentrations, but also facilitate
downstream processing. As an example, the production of several vicinal diols was possible in a 2-step 1-pot cascade in micro-aqueous organic solvents with product concentration up to 440 mM and space-time-yields up to 330 g L-1 d-1 (ee/de >99 %). Novel set-ups of this system include coproduct recycling as well as in situ product removal.
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