•Combining the “two worlds” biocatalysis and chemocatalysis towards one-pot syntheses in aqueous media is a promising concept for the development of both economically and ecologically advantageous ...production processes.•Water is an attractive solvent due to its environmental friendliness, lack of toxicity, low cost, and the opportunity it provides (as the solvent in nature) to apply the full range of enzymes.•Synthetic “proof of concepts” for a range of combinations of biotransformations with metal catalysts as well as organocatalysts in aqueous reaction medium has been successfully demonstrated.
The combination of biocatalytic and chemocatalytic reactions leading to one-pot processes in aqueous medium represents an economically and ecologically attractive concept in organic synthesis due to the potential to avoid time and capacity consuming and waste producing work-up steps of intermediates. The use of water as a solvent has many advantages. A key feature is the opportunity it provides as the solvent in nature to make use of the full range of enzymes. In recent years development of chemoenzymatic one-pot processes in water has emerged tremendously, and proof of concepts for the combination of biotransformations with metal catalysts and organocatalysts were demonstrated. This review will focus on major contributions in this field, which also underline the compatibility of these two ‘worlds’ of catalysis with each other as well as the industrial potential of this one-pot approach.
Chemoenzymatic catalysis, by definition, involves the merging of sequential reactions using both chemocatalysis and biocatalysis, typically in a single reaction vessel. A major challenge, the ...solution to which, however, is associated with numerous advantages, is to run such one-pot processes in water: the majority of enzyme-catalyzed processes take place in water as Nature’s reaction medium, thus enabling a broad synthetic diversity when using water due to the option to use virtually all types of enzymes. Furthermore, water is cheap, abundantly available, and environmentally friendly, thus making it, in principle, an ideal reaction medium. On the other hand, most chemocatalysis is routinely performed today in organic solvents (which might deactivate enzymes), thus appearing to make it difficult to combine such reactions with biocatalysis toward one-pot cascades in water. Several creative approaches and solutions that enable such combinations of chemo- and biocatalysis in water to be realized and applied to synthetic problems are presented herein, reflecting the state-of-the-art in this blossoming field. Coverage has been sectioned into three parts, after introductory remarks: (1) Chapter 2 focuses on historical developments that initiated this area of research; (2) Chapter 3 describes key developments post-initial discoveries that have advanced this field; and (3) Chapter 4 highlights the latest achievements that provide attractive solutions to the main question of compatibility between biocatalysis (used predominantly in aqueous media) and chemocatalysis (that remains predominantly performed in organic solvents), both Chapters covering mainly literature from ca. 2018 to the present. Chapters 5 and 6 provide a brief overview as to where the field stands, the challenges that lie ahead, and ultimately, the prognosis looking toward the future of chemoenzymatic catalysis in organic synthesis.
A Wacker oxidation using CuCl/PdCl2 as a catalyst system was successfully combined with an enzymatic ketone reduction to convert styrene enantioselectively into 1‐phenylethanol in a one‐pot process, ...although the two reactions conducted in aqueous media are not compatible due to enzyme deactivation by Cu ions. The one‐pot feasibility was achieved via compartmentalization of the reactions. Conducting the Wacker oxidation in the interior of a polydimethylsiloxane thimble enables diffusion of only the organic substrate and product into the exterior where the biotransformation takes place. Thus, the Cu ions detrimental to the enzyme are withheld from the reaction media of the biotransformation. In this one‐pot process, which formally corresponds to an asymmetric hydration of alkenes, a range of 1‐arylethanols were formed with high conversions and 98–99 % ee. In addition, the catalyst system of the Wacker oxidation was recycled 15 times without significant decrease in conversion.
Dream reaction: A Wacker oxidation with PdCl2/CuCl was combined with an enzymatic reduction to convert styrenes enantioselectively to 1‐phenylethanols in a one‐pot process, although the two reactions are not compatible with each other due to enzyme deactivation by Cu ions. The key to success was the compartmentalization of the catalysts (see picture; PDMS=polydimethylsiloxane).
The development of enantioselective syntheses of nitriles gained increasing interest due to, e.g., an increasing demand for chiral nitriles for drug synthesis. Complementing existing routes, recently ...catalytic processes enabling an enantioselective formation of the chiral nitrile moiety without the need to utilize cyanide were accomplished. It is noteworthy that these processes are complementary to each other as they are based on different types of substrates, catalytic methods (utilizing chemo- and biocatalysts), and stereochemical reaction concepts (asymmetric synthesis versus resolution).
The Strecker reaction which was reported already in 1850 is the oldest known synthesis of alpha-amino acids. This reaction comprises a condensation of an aldehyde, ammonia, and cyanide source, ...followed by subsequent hydrolysis of the resulting alpha-amino nitrile.
While belonging to the most fundamental functional groups, nitriles represent a class of compound that still raises challenges in terms of an efficient, cost‐effective, general and, at the same time, ...sustainable way for their synthesis. Complementing existing chemical routes, recently a cyanide‐free enzymatic process technology based on the use of an aldoxime dehydratase (Oxd) as a biocatalyst component has been developed and successfully applied for the synthesis of a range of nitrile products. In these biotransformations, the Oxd enzymes catalyze the dehydration of aldoximes as readily available substrates to the nitrile products. Herein, these developments with such enzymes are summarized, with a strong focus on synthetic applications. It is demonstrated that this biocatalytic technology has the potential to “cross the bridge” between the production of fine chemicals and pharmaceuticals, on one hand, and bulk and commodity chemicals, on the other.
Nitrile synthesis with enzymes: An overview of a biocatalytic process technology suitable for the efficient and cyanide‐free synthesis of nitriles by means of dehydration of aldoximes in water is given. A broad range of nitriles are obtained in such biotransformations. Chiral nitriles can be obtained in high enantiomeric excess. The aldoxime substrates are readily available by condensation of aldehydes with NH2OH.
•Different strategies to regenerate the reduced coenzymes NAD(P)H are presented.•Besides two standard methods this contribution focusses on a further method used rarely so far.•This method referred ...to as “closed-loop” or “self-sufficient” method is illustrated by several examples.•Neither an additional substrate nor a further regenerating enzyme are required for this regenerating method.•The current status as well as advantages and disadvantages of this method are discussed.
Biocatalytic reduction reactions depending on nicotinamide coenzymes require an additional reaction to regenerate the consumed cofactor. For preparative application the preferred method is the simultaneous coupling of an in situ regeneration reaction. There are different strategically advantageous routes to achieve this goal. The standard method uses a second enzyme and a second co-substrate, for example formate and formate dehydrogenase or glucose and glucose dehydrogenase. Alternatively, a second substrate is employed which is converted by the same enzyme used for the primary reaction. For example, alcohol dehydrogenase catalyzed reactions are often coupled with excess 2-propanol which is oxidized to acetone during the regeneration of NAD(P)H. A third method utilizes a reaction-internal sequence by the direct coupling of an oxidizing and a reducing enzyme reaction. Neither an additional substrate nor a further regenerating enzyme are required for the recycling reaction. This kind of “closed-loop” or “self-sufficient” redox process for cofactor regeneration has been used rarely so far. Its most intriguing advantage is that even redox reactions with unstable precursors can be realized provided that this compound is produced in situ by an opposite redox reaction. This elegant method is applicable in special cases only but increasing numbers of examples have been published during the last years.
A biocatalytic approach toward linear aliphatic nitriles being widely used as industrial bulk chemicals has been developed that runs at high substrate loadings of up to 1.4 kg/L as demonstrated for ...the synthesis of n-octanenitrile. This substrate loading is one of the highest ever reported in biocatalysis and to best of our knowledge the highest obtained for a water-immiscible product in aqueous medium. It is noteworthy that the biotransformation at such a high substrate loading was achieved by means of a metalloprotein bearing an iron-containing heme subunit in the active site. In detail, an aldoxime dehydratase from Bacillus sp. OxB-1 was used as a biocatalyst for a dehydration of aldoximes as readily available starting materials due to their easy preparation from aliphatic aldehydes through spontaneous condensation with hydroxylamine as bulk chemical. Excellent conversions toward the nitriles in the two-phase system were achieved and the products are easily separated from the reaction mixture without the need for further purification. Aliphatic nitriles are used in industry as solvents and intermediates for the production of surfactants and life sciences products.
In recent years vanadium catalysis has been extended to a range of different and even complementary directions in asymmetric synthesis. Inspired by nature’s way to activate both substrate and reagent ...in many cases, the design of efficient bifunctional and dinuclear vanadium catalysts has been achieved. Furthermore, vanadium catalysis has been an early field in which “hybrid catalysts” have been studied in detail by incorporation of oxovanadium complexes into proteins, thus giving artificial enzymes. In addition, a high compatibility of vanadium with proteins enabled the use of vanadium chemocatalysts for combinations with enzyme catalysis in one‐pot, thus leading to dynamic kinetic resolutions. In this contribution, these three concepts of vanadium catalysis opening up new perspectives for asymmetric synthesis are reviewed.
Vanadium catalysis successfully extended: Inspired by nature's way to activate substrates and reagents, bifunctional and dinuclear vanadium catalysts for CC coupling have been designed. In addition, vanadium catalysis was “merged” with protein chemistry by developing “hybrid catalysts” through incorporation of vanadium into enzymes and by combining vanadium chemocatalysts with enzymes in the dynamic kinetic resolution of alcohols.
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