Application of Ketoreductase in Asymmetric Synthesis of Pharmaceuticals and Bioactive Molecules: An Update (2018–2020)

Abstract

With the rapid development of genomic DNA sequencing, recombinant DNA expression, and protein engineering, biocatalysis has been increasingly and widely adopted in the synthesis of pharmaceuticals, bioactive molecules, fine chemicals, and agrochemicals. In this review, we have summarized the most recent advances achieved (2018–2020) in the research area of ketoreductase (KRED)‐catalyzed asymmetric synthesis of chiral secondary alcohol intermediates to pharmaceuticals and bioactive molecules. In the first part, synthesis of chiral alcohols with one stereocenter through the bioreduction of four different ketone classes, namely acyclic aliphatic ketones, benzyl or phenylethyl ketones, cyclic aliphatic ketones, and aryl ketones, is discussed. In the second part, KRED‐catalyzed dynamic reductive kinetic resolution and reductive desymmetrization are presented for the synthesis of chiral alcohols with two contiguous stereocenters.

Alcohol Dehydrogenases as Catalysts in Organic Synthesis

“…The aim of this contribution is to present the current state-of-the-art of ADHs in organic synthesis. It builds on and extends previous review articles covering various aspects of ADH catalysis (Li et al, 2021c;de Gonzalo and Paul, 2021;Hollmann et al, 2021;Musa et al, 2021;Musa, 2022).…”

Preparation of chiral aryl alcohols: a controllable enzymatic strategy via light-driven NAD(P)H regeneration

“…Among these practical examples of biocatalysis, the application of ketoreductases (KREDs) to catalyze the reduction of ketones to the corresponding chiral alcohols is a common and effective method, which has a broad substrate spectrum and high selectivity under mild conditions. 3 A variety of KREDs have been successfully applied to the industrial production of pharmaceutical intermediates, such as a-lipoic acid, duloxetine, vibegron (Fig. 1) and more.…”

“…1) and more. [2][3][4] However, using KREDs as catalysts for the synthesis of chiral alcohols still has some intrinsic limitations, such as low catalytic activity toward non-natural substrates and high cost of enzyme-specific cofactors (NAD(P)H), the latter representing the key disadvantage in the industrialization of the production of many promising enzyme processes. 5,6 Until now, scientists have developed a variety of cofactor regeneration methods, including enzymatic, chemical, electrochemical and lightdriven regeneration methods.…”

Ketoreductase Catalyzed (Dynamic) Kinetic Resolution for Biomanufacturing of Chiral Chemicals

“…Ketoreductases catalyzed reductions of ketones into chiral alcohols are the widely used and important biocatalytic reactions ( Kaluzna et al, 2005a ; Brenna, 2013 ; Hollmann et al, 2021 ; Li et al, 2021 ; Musa, 2022 ). The increasing studies on protein engineering or directed evolution (the Nobel prize in chemistry 2018) ( Arnold, 2019 ) of KREDs, and combining KREDs with other catalysts, such as biocatalysts, metal catalysts (the Nobel prize in chemistry 2001) ( Noyori, 2002 ), organocatalysts (the Nobel prize in chemistry 2021) ( Hargittai, 2022 ), and photocatalysts ( DeHovitz et al, 2020 ), further encourage the application of KREDs in asymmetric synthesis.…”