Enzyme‐Catalyzed Asymmetric Reduction of Ketones

Abstract

The enantioselective transformation of a prochiral C=O double bond into the corresponding reduced CH–OH single bond plays a major role in asymmetric synthesis since this type of transformation represents a straightforward and an atom‐economical approach toward the synthesis of optically active alcohols. Owing to the importance of chiral alcohols in the field of chiral drug production, enantioselective ketone reduction also gained tremendous industrial interest. For the enantioselective reduction of ketones, numerous efficient catalytic routes have been developed up‐to‐date. As outstanding chemocatalytic technologies, metal‐catalyzed asymmetric hydrogenation of ketones and borane reduction are widely applied on industrial scale. Complementing these chemocatalytic technologies for the production of enantiomerically pure alcohols, enantioselective biocatalytic reduction of ketones turned out to be a highly efficient and competitive alternative technology. Notably, biocatalytic ketone technologies already made the “jump” from an interesting academic synthetic tool toward an industrially feasible technology platform. Besides high catalytic efficiency and excellent enantioselectivities, robustness and industrial large‐scale feasibility are further key features of enantioselective ketone reduction processes with biocatalysts. Thus, it is no surprise that the suitability for industrial purpose, in particular, for large‐scale manufacture of enantiomerically pure alcohols as drug intermediates, has been already demonstrated by a broad range of technical applications in the chemical and pharmaceutical industry.

Status check: biocatalysis; its use with and without chemocatalysis. How does the fine chemicals industry view this area?

“…13,14 A further success story of biocatalysis in asymmetric synthesis is related to the industrial production of chiral alcohols. 15,16 While originally performed via impressive Noyori-type hydrogenations, 17 the last two decades have produced an increasing number of asymmetric biocatalytic ketone reductions made available to the fine chemicals area and especially, the pharmaceutical industry. 15,16 This biocatalytic ketone reduction technology can be run at very high substrate loadings, 18 and hence, has become very competitive with, and in some cases outperforming, asymmetric metal-catalyzed hydrogenations.…”

Integrating Whole Cell Biotransformation of Aroma Compounds into a Novel Biorefinery Concept

“…For the enzymatic reduction of EAA to E3HB, the regeneration of the cofactor is necessary (Figure 2) because its supply in a stoichiometric amount would be too expensive. The two main methods for cofactor regeneration are the substrate-coupled and the enzyme-coupled regeneration [17]. In principle, regeneration can also be carried out photochemically, electrochemically, or chemically using a catalyst which is regenerating the enzyme [18].…”

Asymmetric Hydroboration of Ketones by Cooperative Lewis Acid–Onium Salt Catalysis: A Quantum Chemical and Microkinetic Study to Combine Theory and Experiment

“…The catalyst − provides exceptional catalytic turnover numbers and high enantioselectivity. The catalytic asymmetric reduction of ketones is an important reaction type producing enantioenriched secondary alcohols, which are valuable building blocks for the synthesis of bioactive compounds. − One of the most popular methods for catalytic asymmetric reductions is the enantioselective hydroboration. − Some years ago, Peters et al introduced the concept of asymmetric bifunctional Lewis acid/aprotic onium salt catalysis, and since then, this concept has demonstrated its utility in various reaction classes such as formal [2 + 2] cycloadditions, − S N reactions, and 1,2-additions. , In the highly enantioselective hydroborations of ketones, this concept allowed for unprecedented productivity. TONs up to 15 400 were achieved, whereas typical TONs in the literature are <100 …”