Biocatalytic ketone reduction—a powerful tool for the production of chiral alcohols—part I: processes with isolated enzymes

Abstract

Enzymes are able to perform reactions under mild conditions, e.g., pH and temperature, with remarkable chemo-, regio-, and stereoselectivity. Because of this feature, the number of biocatalysts used in organic synthesis has rapidly increased during the last decades, especially for the production of chiral compounds. The present review highlights biotechnological processes for the production of chiral alcohols by reducing prochiral ketones. These reactions can be catalyzed by either isolated enzymes or whole cells that exhibit ketone-reducing activity. The use of isolated enzymes is often preferred because of a higher volumetric productivity and the absence of side reactions. Both types of catalysts have also deficiencies limiting their use in synthesis of chiral alcohols. Because reductase-catalyzed reactions are dependent on cofactors, one major task in process development is to provide an effective method for regeneration of the consumed cofactors. In this paper, strategies for cofactor regeneration in biocatalytic ketone reduction are reviewed. Furthermore, different processes carried out on laboratory and industrial scales using isolated enzymes are presented. Attention is turned to process parameters, e.g., conversion, yield, enantiomeric excess, and process strategies, e.g., the application of biphasic systems or methods of in situ (co)product recovery. The biocatalytic production of chiral alcohols utilizing whole cells is presented in part II of this review.

Engineered enzymes for chemical production

“…Davis et al (2006) disclosed a route to a hydroxynitrile ester combining an asymmetric ketone reduction with a cyanation step. In the first step, ethyl-4-chloroacetoacetate is reduced by a ketone reductase (KRED, or alcohol dehydrogenase, ADH (Goldberg et al, 2007)). The regeneration of the cofactor is achieved with addition of glucose and glucose dehydrogenase (GDH).…”

Rapid asymmetric reduction of ethyl 4-chloro-3-oxobutanoate using a thermostabilized mutant of ketoreductase ChKRED20

“…The reaction is generally catalyzed with microorganisms producing carbonyl reductases (or ketone reductases, KRED) or recombinant enzymes coupled with a proper cofactor regeneration system (Bornscheuer et al 2012;Hollmann et al 2011;Huisman et al 2010;Moore et al 2007;Ni and Xu 2012;Patel 2008). The recombinant enzymes are particularly preferred in recent industrial-scale setups for easy scale-up with high volumetric productivity, as well as the absence of side reactions (Goldberg et al 2007;Huisman et al 2010). In addition, when significant improvement of catalytic properties is demanded, the recombinant enzymes can always be engineered via directed evolution to meet the process requirements.…”

Chiral pesticides

“…106) Recently, the biocatalytic production of chiral alcohols utilizing isolated enzymes and whole cells has been reported. [107][108] …”