Biocatalytic cascades

Resch, V., Fabian, W.M.F., and Kroutil, W. (2010) Deracemisation of mandelic acid to optically pure non-natural L-phenylglycine via a redox-neutral biocatalytic cascade. Adv. Synth. Catal., 352 (6), 993-997. 

Sequential biocatalytic cascade reactions are characterized by the use of multiple enzymatic steps involving various biocatalysts. One cascade reaction can consist of an enzyme-module with several enzymes if substrate and inhibitor kinetics are compatible with these combinations. Sequential use of such enzyme-modules surpassing the work-up of intermediate products is the criterion for the idea of cascade reactions we address here on the one hand, the synthesis of nucleotide sugars and their derivatives, on the other hand, the synthesis of glycan epitopes with multiple GTs. 

It has been widely demonstrated that aldolases are important biocatalysts for the asymmetric carbon-carbon bond formation. This is because they possess the unique characteristics by which they can build up new polyfunctional molecular frameworks through the assembly of simple molecules. Particularly important in this point is to design biocatalytic cascade carboligation reactions by a sequential or one-pot combination of independent aldol additions catalyzed by different... 

Fig. 4 (A) The biocatalytic cascade used for the logic processing of the biomarkers characteristic of liver injury, resulting in situ pH changes and activation of the electrode interface. (B) pH Changes generated in situ by the biocatalytic cascade activated with various combinations of the two biomarker input signals, ALT, LDH (a) 0,0 (b) 0,1 (c) 1,0 (d) 1,1. The dotted line corresponds to the pK value of the P4VP-brush. (C) Cyclic voltammograms obtained for the ITO electrode modified with the P4VP-polymer brush in (a) the initial OFF state, pH 6.3, and (b) the ON state enabled by the ALT, LDH input combination 1,1, pH 4.75. (Adapted from ref. 89, with permission Copyright American Chemical Society, 2011).

Shifting the equilibrimn of a biocatalytic cascade synthesis to enantiopure epoxides using anion exchangers. Tetrahedron ... 

Asymmetry, 20,483-488 (c) Schrittwieser, 74 J.H., Lavandera, L, Seisser, B., Mautner, B., and Kroutil, W. (2009) Biocatalytic cascade for the synthesis of enantiopure beta-azidoalcohols and beta-hydroxynitriles. Eur. 

Scheme 11.3 Deracemization of secondary alcohols by a biocatalytic cascade using Alcaligenes faecalis who e cells in the oxidation step and an ADH with opposite stereoselectivity in the reduction step.

Scheme 11.6 Biocatalytic cascade isomerization of cyclohexenol into cyclohexanone by an ADH/ ER system. Undesired side reaction (reduction of cyclohexanone into cyclohexanol) is shown with a dashed arrow.

The biocatalytic cascade was also demonstrated for the oxidative N-dealkylation of various secondary benzylamine derivatives, which usually requires harsh conditions (Scheme 2.45). All investigated substrates (R = Me, Et, 2-Pr) were transformed to completion (conv. >99%) giving the unprotected amine under mild reaction conditions. Notably, the already existing toolbox of tailored MAO-Ns implies that this method is not limited to such simple aryl-alkyl systems but represents a general method for N-deprotection. 

Biocatalysis has been established as an enviroiunentally friendly and sustainable alternative to conventional chemical processes in the pharmaceutical industry in the recent decade. Advances in recombinant DNA and genomics technologies, protein and metabolic engineering, as well as bioinformatics are critical in the discovery and development of biocatalysts for industrial processes. Significant progress has also been made in our ability to design biocatalytic cascades and to combine them with traditional chemocatalytic routes. The opportunities and combinations are endless. 

Much progress has been made using the concepts described in the previous section to implement new biocatalytic cascades. The vast majority of these have been examined at laboratory scale, but the following list gives a representative picture of the current state of the art. The cascades are divided into classes, according to the definitions described earlier. 

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