Enzyme Catalysis in Organic Synthesis, Third Edition

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... Nowadays, the biocatalytic processes promoted by whole cells or isolated enzymes represent one of the most heavily used green methodologies in preparative chemistry to perform highly chemo-, regio-, and stereoselective organic transformations, as they are typically run under very mild reaction conditions (e.g., almost neutral pH buffer solutions, ambient temperature or mild heating, atmospheric pressure, etc.) [1,2]. Isolated enzymes are certainly specific catalysts for such transformations, with a history of high cost-effectiveness, especially on a preparative scale [3]. Whole-cell microorganisms, on the other hand, offer several positive features associated with their use as biocatalysts as they are more accessible, stable and easier to handle [4]. ...
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Biocatalytic processes are increasingly playing a key role in the development of sustainable asymmetric syntheses, which are central to pharmaceutical companies for the production of chiral enantiopure drugs. This work describes a simple and economically viable chemoenzymatic process for the production of (S)-rivastigmine, which is an important drug for the treatment of mild to moderate dementia of the Alzheimer’s type. The described protocol involves the R-regioselective bioreduction of an aromatic ketone by Lactobacillus reuteri DSM 20016 whole cells in phosphate buffered saline (PBS) (37 °C, 24 h) as a key step. Biocatalytic performance of baker’s yeast whole cells in water and in aqueous eutectic mixtures have been evaluated and discussed as well. The route is scalable, environmentally friendly, and the target drug is obtained via four steps in overall 78% yield and 98% ee.
... 183 A variety of chiral amines can be obtained with high to very high enantioselectivities. Several transformations have been developed and were carried out on a 100 kg scale, 184 however, application to small-scale synthetic problems especially for more elaborate targets is not practical because the optimization of the enzyme and reactions condition are very time consuming. Alternative methods such as the asymmetric reductive acylation of ketoximes by enzyme-metal cocatalysis 185 or the use of artificial transfer hydrogenases consisting of an achiral metal complex combined with streptavidine 186 are still in an emerging state (see Chapter 8.08). ...
This chapter presents a critical overview on the enantioselective hydrogenation and transfer hydrogenation of various CæN functions catalyzed by chiral organometallic catalysts. After a short description of the most effective metal complexes and chiral ligands, results are presented for reduction of the following substrate classes: N-aryl imines, N-alkyl imines, primary imines, endocyclic imines (including iminium derivatives), N-heteroarenes, and CæN-X compounds proceeding with synthetically useful enantioselectivities (usually >90% ee). It is concluded that the choice of the metal and the ligand has to be adapted for every individual transformation but that existing results allow the identification of catalytic systems with an above average chance for success. Mechanistic considerations and the applications of asymmetric CæN reductions to the synthesis of molecules of industrial or biological interest are described in some detail. Alternative reduction methods for CæN functions such as organocatalytic transfer hydrogenation, hydride reductions, hydrosilylation, and biocatalysis are being addressed briefly.
Candida antarctica (CAL‐B) lipase‐catalyzed resolution of 1,3‐dialkyl‐3‐hydroxymethyl oxindoles has been performed to obtain (R)‐1,3‐dialkyl‐3‐acetoxymethyl oxindoles with up to 99% ee and (S)‐1,3‐dialkyl‐3‐hydroxymethyl oxindoles with up to 78% ee using vinyl acetate as acylating agent and acetonitrile as solvent transforming (S)‐3‐allyl‐3‐hydroxymethyl oxindole to (3S)‐1′‐benzyl‐5‐(iodomethyl)‐4,5‐dihydro‐2H‐spiro[furan‐3,3′‐indolin]‐2′‐one. The optically active 3‐substituted‐3‐hydroxymethyl oxindoles and spiro‐oxindoles are among the key synthons in the synthesis of potentially biologically active molecules.
From the biocatalysis point of view, the production of chiral amines has been restricted, for years, to kinetic and dynamic resolution processes mediated by lipases. Recently, impelled by the growth of the genetic engineering field, the toolbox of chiral amines synthesis has expanded and other enzymes have been domesticated, such as transaminases (TAs), imino reductases (IREDs), and mono‐amino oxidases. Among the numerous enzymes that have been applied to reactions in order to obtain enantiomerically pure amines, hydrolases are the most widespread, since they are useful biocatalysts for the resolution of racemates, leading to the synthesis of enantiopure chiral drug intermediates. TAs belong to fold types I and IV of pyridoxal 5'‐phosphate‐dependent enzymes and can catalyze the reversible transfer of an amino group from a suitable donor to a carbonyl acceptor. IREDs are oxidoreductases that catalyze the asymmetric reduction of prochiral imines to amines using nicotinamide adenine dinucleotide phosphate as the hydride source.
In 2012, David Rozzell published an excellent and concise survey of commercial enzyme suppliers. This chapter includes details of companies that provide one or more of the many services focused towards bioprocess development. This survey is primarily aimed at the industrial and academic synthetic chemist who needs to source enzymes or services for biocatalytic process development. The chapter presents a table regarding commercial enzyme suppliers and distributors, providing information on enzyme name, supplier, company contact details, and attributes. It also presents a table that gives details on bioprocess service providers, providing company name and website. The chapter includes a list of the chemical transformations of selected commercially available enzymes.
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