biocatalysis —key to sustainable industrial chemistry

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Available online at www.sciencedirect.com

Biocatalysis key to sustainable industrial chemistryRoland WohlgemuthThe ongoing trends to process improvements, cost reductions and increasing quality, safety, health and environment requirements of industrial chemical transformations have strengthened the translation of global biocatalysis research work into industrial applications. One focus has been on biocatalytic single-step reactions with one or two substrates, the identication of bottlenecks and molecular as well as engineering approaches to overcome these bottlenecks. Robust industrial procedures have been established along classes of biocatalytic single-step reactions. Multi-step reactions and multi-component reactions (MCRs) enable a bottom-up approach with biocatalytic reactions working together in one compartment and recations hindering each other within different compartments or steps. The understanding of the catalytic functions of known and new enzymes is key for the development of new sustainable chemical transformations.Address SigmaAldrich, Industriestrasse 25, CH-9470 Buchs, Switzerland Corresponding author: Wohlgemuth, Roland ([email protected])

omical, energy saving, and environment-friendly production procedures. The global needs for clean manufacturing technologies, nonrenewable raw materials, management of hazardous chemicals and waste present new research challenges to both chemistry and biotechnology. These sciences are taking up these challenges and the initiatives in Green/sustainable chemistry [2,3] and white/industrial biotechnology [4] have emerged in their disciplines independently. It is therefore of crucial importance for the success of implementation and translation of science and technology into standard industrial practice to develop a common chemistrybiotechnology interface. One common opportunity for improvement and invention is the current use of protecting groups for overcoming nonselective and incompatible reactivities in synthesis and biomimetic as well as enzyme-catalyzed synthesis can provide the selectivities needed to overcome barriers [5]. The manufacturing of molecular complexity from simple starting materials with a minimum number of steps, avoiding protectiondeprotection loops and orientation towards function of the product attract much interest and biocatalytic process steps are well positioned for contributing to the solutions of the above-mentioned challenges [6]. The creation of sustainable value by viable industrial processes and synthetic pathways requires not only research progress in chemistry and biotechnology, but in addition the integration of research from molecular and engineering sciences, thereby enabling a large range of industrial biotransformations [710]. As reaction development serves different practical needs, progress in the working areas single-step reactions, multi-step reactions, and multi-component reactions (MCRs) will be discussed in the following sections. Despite the enormous achievements in the chemical synthesis of organic compounds, once believed to be accessible only by biological processes and vital forces, over the past two centuries, many present state-of-the-art processes are highly inefcient [3]. This and additional boundary conditions like safety, health and environment issues in industrial processes have revitalized the interest in the discovery/invention of novel biocatalytic reactions and reaction methodologies, which have been evolved by nature to achieve highly efcient and selective transformations. Therefore the section on the development of new biocatalytic reaction methodology addresses this important industrial innovation area.

Current Opinion in Biotechnology 2010, 21:713724 This review comes from a themed issue on Chemical biotechnology Edited by Phil Holliger and Karl Erich Jaeger Available online 26th October 2010 0958-1669/$ see front matter # 2010 Elsevier Ltd. All rights reserved. DOI 10.1016/j.copbio.2010.09.016

IntroductionThe creation of value-added products by chemical transformations has contributed signicantly to the quality of life over the centuries and has reached a high level, but it has been suggested that many of the stoichiometric reactions in current use should be replaced by catalytic processes [1]. Although catalytic tools are not only a cornerstone of our present economy and society, but also a key feature of basic life processes, most of the catalysts used in the automotive, fuel rening, and chemical industries consist either of inorganic, organometallic or of organic catalysts in heterogeneous form, as for example, catalysts involved in pollutant removal from the exhaust leaving the car engines. The use of biocatalysts in chemical transformations has really taken off with the focus on safe, healthy, resource efcient and econwww.sciencedirect.com

Industrial biocatalytic single-step reactionsThe early success of single biocatalytic reaction steps in classical organic synthesis schemes has led to anCurrent Opinion in Biotechnology 2010, 21:713724

714 Chemical biotechnology

increasing number of established industrial processes and continues to be a useful approach for the introduction of biocatalysis into industrial practice. The discovery and development of novel biocatalytic reaction steps can thereby focus on overcoming synthetic bottleneck reactions and improving the performance of existing chemical reactions according to industrial requirements. Biocatalytic versions of reactions which are impossible or impractical by existing chemistry tools generate high interest and stimulate further process research and development work in industry.

active nitrile products in high yields and excellent enantioselectivities [20].Amination reactions

Oxidation and reduction reactions

Oxidations and reductions catalyzed by oxidoreductases have progressed towards the tools of choice (Figure 1) due to their improved performance with respect to reaction selectivity, safety, health, and environment aspects. Selective introduction of one or two oxygen atoms by biocatalysts has continued to attract a lot of industrial interest. Among the reactions introducing one oxygen atom, selective asymmetric hydroxylations, epoxidations, and BaeyerVilliger oxidations [1113,14] have made signicant progress and are of interest for the oxyfunctionalization of inexpensive organic building blocks. Selective biocatalytic oxidations of one out of several hydroxygroups, as for example, in alcohols and sugars, continue to be of industrial interest since the thirties of the last century and have additional sustainability benets compared to the classical chemical oxidations [7]. Since classical chemical oxidations often use stoichiometric oxidants in excess, the selective removal of remaining oxidants is decisive for the product quality and enzymatic methods have become standard practice in production. Depending on the enzyme properties and the cofactor recycling system, both the oxidative and the reductive directions of an oxidoreductase application are of interest [15,16]. Sustainable enzymatic reductions of aldehydes and ketones are reliable, scalable and inexpensive routes to optically active alcohols and have been extensively employed in organic synthesis despite the vast number of asymmetric reductions [17]. Even in the area of the reduction of carboncarbon double bonds, where catalytic hydrogenation with hydrogen gas in autoclaves is performed routinely, new asymmetric biocatalytic reductions of activated alkenes bearing an electron-withdrawing group have become interesting methods for preparing the corresponding saturated products in up to >99% ee and for side stepping the use of hydrogen gas [18]. High enantioselectivity was also observed for the asymmetric reduction of activated a,b-unsaturated enones catalyzed by pentaerythritol tetranitrate reductase for reaction product stereogenic centers at the beta-carbon atom [19]. Enoate reductases have also been used for the conversion of a series of a,b-unsaturated nitriles to the opticallyCurrent Opinion in Biotechnology 2010, 21:713724

As in nature, industrial biocatalytic aminations have been performed by the two different routes of transamination and reductive amination. The use of amino acid dehydrogenases in reductive amination of prochiral precursors continues to play an important role in the enzymatic production of D-enantiomers and L-enantiomers of both natural and non-natural amino acids. Transaminases have obtained increased interest for the asymmetric synthesis of amines from prochiral ketones [2124] and amination is becoming a key reaction (Figure 2) in industrial biotransformations [9]. New routes to nonchiral amines are also of interest and a new biocatalytic transamination of pyridoxal-50 -phosphate has been achieved with complete conversion [25]. The efciency of the manufacturing process for the antidiabetic compound sitagliptin has been greatly improved by replacing the Rh(Jobiphos)catalyzed asymmetric hydrogenation of an enamine at high pressure with a direct transaminase-catalyzed amination of prositagliptin ketone [26]. The best engineered enzyme could convert 200 g/l prositagliptin ketone to sitagliptin with an excellent ee of >99.95%. A 53% productivity increase, 19% waste reduction, elimination of heavy metals, cost reductions and avoiding specialized high-pressure hydrogenation equipment have been found as specic advantages of the biocatalytic process [26].Glycosylation reactions

As selective chemical glycosylation reactions require a substantial synthetic effort involving various protecting group chemistries in organic solvents, the use of glycosyltransferases for coupling glycosyl donors to nonprotected acceptors in aqueous media (Figure 3) continues to attract a lot of interest [2729]. Methods based on the application of glycosyltransferases are