Multistep enzyme cascades as a route towards green and sustainable pharmaceutical syntheses

Enzyme cascades are a powerful technology to develop environmentally friendly and cost-effective synthetic processes to manufacture drugs, as they couple different biotransformations in sequential reactions to synthesize the product. These biocatalytic tools can address two key parameters for the pharmaceutical industry: an improved selectivity of synthetic reactions and a reduction of potential hazards by using biocompatible catalysts, which can be produced from sustainable sources, which are biodegradable and, generally, non-toxic. Here we outline a broad variety of enzyme cascades used either in vivo (whole cells) or in vitro (purified enzymes) to specifically target pharmaceutically relevant molecules, from simple building blocks to complex drugs. We also discuss the advantages and requirements of multistep enzyme cascades and their combination with chemical catalysts through a series of reported examples. Finally, we examine the efficiency of enzyme cascades and how they can be further improved by enzyme engineering, process intensification in flow reactors and/or enzyme immobilization to meet all the industrial requirements.