Abstract

Nature has had many generations to optimise its catalytic processes. As a result they are both extremely efficient and exquisitely selective. Biocatalysis is now very much a mainstay of industrial organic synthesis, particularly with the advent of protein engineering and directed evolution enabling the preparation of robust enzymes fine-tuned to a particular substrate. The importance of this technology was recognised in 2018 with the award of the chemistry Nobel prize to Frances Arnold for her pioneering work on directed evolution of enzymes. Despite significant advances, biocatalysis is limited to natural chemical reactions, precluding its wide application in general synthetic chemistry, where small molecule catalysts still have the upper hand. That said the repertoire of “unnatural” enzyme mediated transformations is increasing, particularly with engineered metalloenzyme systems. This article describes how development of new to Nature chemistry is evolving and what lies on the horizon.

---

As the complexity of drug molecules increases, so the synthetic challenges become more pointed. In addition, increasing demand for green, atom-economic and sustainable methods of manufacture with low environmental impact introduce another level of complexity (1). This coupled with shortened development timelines and demand for lower cost medicines has prompted a reckoning with Nature, and as such the use of enzymes and biocatalytic processes for mainstream synthesis of complex organic substrates, particularly chiral molecules, has increased significantly over recent years. The introduction of protein engineering and- in a Darwinian parody- genetic mutation and the evolutionary selection of a particular favourable reaction trait (robustness, selectivity, solvent stability etc.) the fine tuning and optimization of an enzyme for a particular chemical transformation is now readily achievable. The historical approach of finding a wildtype enzyme that’s available to get you as close as possible to the required conversion and selectivity (but never quite close enough) is now a thing of the past. Notable examples of the success of such an approach is the directed evolution of a transa ...