Opportunities and challenges for combining chemo- and biocatalysis

Abstract

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][2][3][4][5][6][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 catalysts 8 . 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 isomerization 9 . 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 group 10,11 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][13][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 reduction 15 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 enzymes 3 . 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 ...

Chemoenzymatic Synthesis of O‐Containing Heterocycles from α‐Diazo Esters

“…While it is well known that the reduction of carbonyl compounds with enzymes usually occurs with high chemo‐ and stereoselectivity, to the best of our knowledge, no enzymatic reduction of keto‐α‐diazoesters has been reported yet. Such a biocatalytic approach would also have the advantage of meeting the growing interest in the development of cost‐effective and environmentally friendly chemical processes . In fact, biocatalytic reactions have already been reported in order to obtain oxygen‐containing heterocycles .…”

Enzyme–Polymer Conjugates as Robust Pickering Interfacial Biocatalysts for Efficient Biotransformations and One‐Pot Cascade Reactions

“…[27] To this end, glucose oxidase (GOx) was chosen for the in situ generation of hydrogen peroxide (from glucose), which is utilized by as econd enzyme,t hus offering the benefits of simple product separation and an excellent ecological profile. BAL-DP75 retained 65 %o fi ts activity upon reuse three times,w hich is significant considering BALv ulnerability at interfaces.…”

Synthesis of Vibegron Enabled by a Ketoreductase Rationally Designed for High pH Dynamic Kinetic Reduction

“…To pursue our retrosynthetic approach (Scheme 2), we first needed to identify aK RED that could produce alcohol 9 from 10.G iven the advances in protein engineering technologies, [11] we envisioned tailoring this enzyme to the required reaction conditions by employing directed evolution with computationally and structurally designed mutations to rapidly create an optimal catalyst. To pursue our retrosynthetic approach (Scheme 2), we first needed to identify aK RED that could produce alcohol 9 from 10.G iven the advances in protein engineering technologies, [11] we envisioned tailoring this enzyme to the required reaction conditions by employing directed evolution with computationally and structurally designed mutations to rapidly create an optimal catalyst.…”