The review compiles artificial cascades involving enzymes with a focus on the last 10 years. A cascade is defined as the combination of at least two reaction steps in a single reaction vessel without ...isolation of the intermediates, whereby at least one step is catalyzed by an enzyme. Additionally, cascades performed in vivo and in vitro are discussed separately, whereby in vivo cascades are defined here as cascades relying on cofactor recycling by the metabolism or on a metabolite from the living organism. The review introduces a systematic classification of the cascades according to the number of enzymes in the linear sequence and differentiates between cascades involving exclusively enzymes and combinations of enzymes with non-natural catalysts or chemical steps. Since the number of examples involving two enzymes is predominant, the two enzyme cascades are further subdivided according to the number, order, and type of redox steps. Furthermore, this classification differentiates between cascades where all reaction steps are performed simultaneously, sequentially, or in flow.
Chiral amines represent a prominent functional group in pharmaceuticals and agrochemicals and are hence attractive targets for asymmetric synthesis. Since the pharmaceutical industry has identified ...biocatalysis as a valuable tool for synthesising chiral molecules with high enantiomeric excess and under mild reaction conditions, enzymatic methods for chiral amine synthesis are increasing in importance. Among the strategies available in this context, the asymmetric reduction of imines by NAD(P)H‐dependent enzymes and the related reductive amination of ketones have long remained underrepresented. However, recent years have witnessed an impressive progress in the application of natural or engineered imine‐reducing enzymes, such as imine reductases, opine dehydrogenases, amine dehydrogenases, and artificial metalloenzymes. This review provides a comprehensive overview of biocatalytic imine reduction and reductive amination of ketones, highlighting the natural roles, substrate scopes, structural features, and potential application fields of the involved enzymes.
Carbon–carbon bond formation is the key reaction for organic synthesis to construct the carbon framework of organic molecules. The review gives a selection of biocatalytic C–C-bond-forming reactions ...which have been investigated during the last 5 years and which have already been proven to be applicable for organic synthesis. In most cases, the reactions lead to products functionalized at the site of C–C-bond formation (e.g., α-hydroxy ketones, aminoalcohols, diols, 1,4-diketones, etc.) or allow to decorate aromatic and heteroaromatic molecules. Furthermore, examples for cyclization of (non)natural precursors leading to saturated carbocycles are given as well as the stereoselective cyclopropanation of olefins affording cyclopropanes. Although many tools are already available, recent research also makes it clear that nature provides an even broader set of enzymes to perform specific C–C coupling reactions. The possibilities are without limit; however, a big library of variants for different types of reactions is required to have the specific enzyme for a desired specific (stereoselective) reaction at hand.
Power of Biocatalysis for Organic Synthesis Winkler, Christoph K; Schrittwieser, Joerg H; Kroutil, Wolfgang
ACS central science,
01/2021, Letnik:
7, Številka:
1
Journal Article
Odprti dostop
Biocatalysis, using defined enzymes for organic transformations, has become a common tool in organic synthesis, which is also frequently applied in industry. The generally high activity and ...outstanding stereo-, regio-, and chemoselectivity observed in many biotransformations are the result of a precise control of the reaction in the active site of the biocatalyst. This control is achieved by exact positioning of the reagents relative to each other in a fine-tuned 3D environment, by specific activating interactions between reagents and the protein, and by subtle movements of the catalyst. Enzyme engineering enables one to adapt the catalyst to the desired reaction and process. A well-filled biocatalytic toolbox is ready to be used for various reactions. Providing nonnatural reagents and conditions and evolving biocatalysts enables one to play with the myriad of options for creating novel transformations and thereby opening new, short pathways to desired target molecules. Combining several biocatalysts in one pot to perform several reactions concurrently increases the efficiency of biocatalysis even further.
The acyl transferase from Mycobacterium smegmatis (MsAcT) catalyzes the acyl transfer between a range of primary and secondary alcohols, whereby its outstanding ability is to perform this reaction in ...aqueous solution. Therefore, MsAcT opens different options for acylation reactions enabling alternatives for many conventionally hydrolytic enzymes used in biocatalysis. Nevertheless, hydrolysis is still a major side reaction of this enzyme. To provide a detailed understanding of the competition between hydrolysis and transesterification reactions, a combination of density functional theory and free energy perturbation methods have been employed. The relative binding free energies and the energy profiles of the chemical steps involved in the reaction were calculated for a number of substrates. The calculations show that the enzyme active site exhibits a higher affinity for substrates with an aromatic ring. The rate-determining step corresponds to the collapse of a negatively charged tetrahedral intermediate in the substrate acylation half-reaction. The intrinsic barriers of the transesterification and hydrolysis half-reactions are calculated to be of similar heights, suggesting that the determining factor in the MsAcT specificity is the higher binding affinity of the active site for the alcohol substrates relative to water. Finally, the influence of the acyl donor on the MsAcT-catalyzed reaction is also investigated by considering different esters in the calculations.
Light has received increased attention for various chemical reactions but also in combination with biocatalytic reactions. Because currently only a few enzymatic reactions are known, which per se ...require light, most transformations involving light and a biocatalyst exploit light either for providing the cosubstrate or cofactor in an appropriate redox state for the biotransformation. In selected cases, a promiscuous activity of known enzymes in the presence of light could be induced. In other approaches, light-induced chemical reactions have been combined with a biocatalytic step, or light-induced biocatalytic reactions were combined with chemical reactions in a linear cascade. Finally, enzymes with a light switchable moiety have been investigated to turn off/on or tune the actual reaction. This Review gives an overview of the various approaches for using light in biocatalysis.
Cytochrome P450 enzymes catalyze a broad set of C–H activation reactions, the most prominent being hydroxylation. This review provides an overview of the regioselectivity (CH
3
-terminal, in-chain, ...and carboxylate-terminal) and the optical purity of the hydroxylation products obtained from fatty acids as far as described, focusing on systems close to preparative application.
Graphical Abstract
The cleavage of alkenes to the corresponding carbonyl products is a widely employed method in organic synthesis, especially to introduce oxygen functionalities into molecules, remove protecting ...groups and tailor large molecules. Chemical methods available for alkene cleavage include, for instance, ozonolysis, several metal‐based variants (KMnO4, OsO4, RuO4, etc.), electrochemical alternatives, singlet oxygen, hypervalent iodine and organic molecules in combination with oxygen. Furthermore, several enzymatic methods for alkene cleavage have been described to establish safe, mild and selective oxidation methods. Various heme and non‐heme iron‐dependent enzymes catalyse the alkene cleavage at ambient temperature and atmospheric pressure in an aqueous buffer, showing good chemo‐ and regioselectivities in selected cases. Quite recently some Cu‐, Mn‐ and Ni‐dependent enzymes have been identified for this reaction. This review gives an overview of the different chemical and enzymatic methods available for the cleavage of alkenes.
Demethylating methyl phenyl ethers is challenging, especially when the products are catechol derivatives prone to follow‐up reactions. For biocatalytic demethylation, monooxygenases have previously ...been described requiring molecular oxygen which may cause oxidative side reactions. Here we show that such compounds can be demethylated anaerobically by using cobalamin‐dependent methyltransferases exploiting thiols like ethyl 3‐mercaptopropionate as a methyl trap. Using just two equivalents of this reagent, a broad spectrum of substituted guaiacol derivatives were demethylated, with conversions mostly above 90 %. This strategy was used to prepare the highly valuable antioxidant hydroxytyrosol on a one‐gram scale in 97 % isolated yield.
Efficient demethylation of methyl phenyl ethers was achieved by biocatalytic O2‐free methyl transfer to thiols forming thio ethers. Since the methyl group is not cleaved from the sulfur under these conditions, the thiol compound acts like a trap driving the reaction towards completion.
Alkaloids are a group of natural products with interesting pharmacological properties and a long history of medicinal application. Their complex molecular structures have fascinated chemists for ...decades, and their total synthesis still poses a considerable challenge. In a previous review, we have illustrated how biocatalysis can make valuable contributions to the asymmetric synthesis of alkaloids. The chemo-enzymatic strategies discussed therein have been further explored and improved in recent years, and advances in amine biocatalysis have vastly expanded the opportunities for incorporating enzymes into synthetic routes towards these important natural products. The present review summarises modern developments in chemo-enzymatic alkaloid synthesis since 2013, in which the biocatalytic transformations continue to take an increasingly 'central' role.
This review article discusses developments in the chemo-enzymatic synthesis of alkaloids since 2013, showcasing how modern methods of organic synthesis and biocatalysis are combined to establish novel routes towards these important natural products.
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