Opportunities and challenges for combining chemo- and biocatalysis

Review Article https://doi.org/10.1038/s41929-017-0010-4 Corrected: Author correction Opportunities and challenges for combining chemo- and biocatalysis Florian Rudroff 1, Marko D. Mihovilovic and Uwe T. Bornscheuer 5* , Harald Gröger 1 , Radka Snajdrova 2 , Hans Iding 3 4 The past decade has seen a substantial increase in successful examples of the combination of chemo- and biocatalysis for multistep syntheses. This is driven by obvious advantages such as higher yields, decreased costs, environmental benefits and high selectivity. On the downside, efforts must be undertaken to combine the divergent reaction conditions, reagent tolerance and solvent systems of these ‘different worlds of catalysis’. Owing to progress in enzyme discovery and engineering, as well as in the development of milder and more compatible conditions for operating with various chemocatalysts, many historical limitations can already be overcome. This Review highlights the opportunities available in the chemical space of combined syntheses using prominent examples, but also discusses the current challenges and emerging solutions, keeping in mind the fast progress in transition metal-, organo-, photo-, electro-, hetero- and biocatalysis. N ature has evolved highly efficient systems in the form of cascade reactions, which assemble the metabolic networks that support life (growth and survival). The basic principle of cascade reactions is also frequently used in biocatalysis, using enzymes in isolation, as well as in combination with chemocatalysts (see Fig. 1 and Box 1 for definition of terms)1–7. As there is no need for purification and isolation of intermediates, operating time, production costs and waste are reduced, and concomitantly, overall yields are improved. In addition, the problem of unstable or difficult to handle intermediates can be overcome, and reactivity as well as selectivity can be enhanced by avoiding unfavourable reaction equilibria through the cooperative effects of multiple catalysts8. Starting in the 1980s, the early examples of the combination of chemo- and biocatalysts were reported by the van Bekkum group, who pioneered the development of a process to make the sugar substitute d-mannitol from readily available d-glucose through the combination of a heterogeneous metal-catalysed hydrogenation and an enzyme-catalysed isomerization9. The first broadly applied technology for the combination of enzyme and metalcatalysts, which was the research subject of many academic groups as well as industry, emerged in the 1990s from the Williams group10,11 and aimed to achieve higher yields than classical kinetic resolution of racemates, thus overcoming the limitation of a maximum yield of 50% in the latter case. A prominent example of work that developed this theme is the combination of lipase-catalysed kinetic resolution via acylation of secondary alcohols with Pd- or Rh-catalysed racemization via reversible transfer hydrogenation to achieve a dynamic kinetic resolution (DKR)12–14. This example was facilitated in part because lipases are active and stable in organic solvents. Later, for instance, Turner’s group combined a monoamine oxidase-catalysed imine formation with a chemical reduction15 to achieve the 100% theoretical yield through a deracemization process. In addition to the combination of metalcatalysis with enzymes, organocatalysis, electrochemistry and light-induced reaction couples have since then been studied extensively, going far beyond the scope of a DKR. The challenges to combining chemo- and biocatalysis in cascades (see Box 1 for definitions and Table 1) can be daunting, not least the requirement for the chemical step to occur in the presence of water, the preferred solvent for enzymes3. This Review therefore highlights recent examples of the combination of chemo- and biocatalysts in aqueous multistep syntheses, and looks at how to overcome limitations by, for example, design of appropriate reaction conditions, protein engineering and advanced reactor concepts. Furthermore, trends such as the integration of transition metalcatalysis into microorganisms and the introduction of novel chemistry into engineered enzymes are discussed, and a critical assessment of the impact of this research field on the chemical and pharmaceutical industry is provided. Finally, cascades combining chemo- and biocatalysis also enable novel synthetic sequences and consequently novel retrosynthetic concepts for the synthesis of complex organic molecules, for example, those required as pharmaceuticals. Thus, they also contribute to the rapidly developing field of retrosynthetic analysis for biocatalysis16–18. This Review should make it easier for chemists to include enzymatic steps in cascade reactions, which in turn will aid the integration of different catalysis disciplines. Concepts In the following sections, we first provide an overview of the concepts using biocatalysis together with different types of chemical catalysis. This is followed by a section dealing with reaction-engineering aspects that enable a suitable combination of several catalytic steps. Combination of (transition) metalcatalysis and biocatalysis. Owing to the availability of numerous efficient metal-catalysed reactions that have reached the ‘mature technology’ stage, their combination with enzymes has historically been dominated especially by the use of transition metals (Fig. 2) as chemocatalyst components. The most frequent example has been DKR, one of the most intensively studied types of chemoenzymatic one-pot cascade Institute of Applied Synthetic Chemistry, TU Wien, Vienna, Austria. 2Organic Chemistry I, Faculty of Chemistry, Bielefeld University, Bielefeld, Germany. Novartis Pharma AG, Basel, Switzerland. 4Process Chemistry and Catalysis, Biocatalysis, F. Hoffmann-La Roche Ltd, Basel, Switzerland. 5Institute of Biochemistry, Department of Biotechnology and Enzyme Catalysis, Greifswald University, Greifswald, Germany. *e-mail: 1 3 12 Nature Catalysis | VOL 1 | JANUARY 2018 | 12–22 | www.nature.com/natcatal © 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. Review Article NaTuRe CaTalysis One-pot cascade reactions Sequential reactions S P S P Concurrent reactions Cat2–n Domino reactions Cat1 Table 1 | Pros and cons for the combination of chemo- and biocatalytic reactions S P Tandem reactions S P Cat2–n Cat1–n Compart. tandem reactions S P Cat2–n Fig. 1 | Definition of different terms for one-pot cascade reactions used in this Review. The sand glass illustrates temporal separation. The number of catalysts is defined from 1 to n. Compartmentalization is depicted with a dashed line and two different colours in the reaction vessel. The domino reaction represents a special form of the concurrent reaction with only one catalytic entity. S, substrate; P, product. Box 1 | Definitions In the literature, different and partially contradicting terms, such as tan (...truncated)