Continuous flow-mode synthesis of (chiral) amines with transaminase: a strategic biocatalytic approach to essential building blocks

Abstract

Chiral amines are essential building blocks to manufacture a plethora of valuable compounds, including active pharmaceutical ingredients (API). It is estimated that about half of the current API contain chiral amines in their structure. However, the current production of chiral amines often involves multi-step synthesis requiring expensive homogeneous catalysts and high energy consumption for subsequent purification. Biocatalytic routes have gained considerable attention in the last decades, as effective and potentially more sustainable alternatives. Indeed, amine transaminases (ATAs) can catalyse transamination reactions and produce chiral amines with excellent enantioselectivity and in mild conditions. Industrial applications of biocatalytic transamination, however, remain scarce as the enzymes often operate in restricted operational conditions and display limited stability. Batch reactors utilizing the free enzyme in solution also face issues regarding catalyst separation, recovery, and reuse. Moreover, the synthesis of most compounds of interest is thermodynamically unfavoured. Taking a side step, catalysis scientists design heterogenized biocatalysts that are more versatile, more stable, and amenable to continuous flow processes. A number of improvement strategies have been deployed: modifications of the transaminase itself (via genetic engineering), optimization of immobilization strategies, design of structured supports, development of integrated equilibrium shifting strategies, concatenation with purification, etc. Here, we summarize and exemplify these advances leading to more efficient biocatalytic systems based on transaminases operating in continuous flow mode.