Molecular Catalysis 541 (2023) 113099 2468-8231/© 2023 Elsevier B.V. All rights reserved. Review Biocatalytic asymmetric reduction of prochiral bulky-bulky ketones Auwal Eshi Sardauna a, 1 , Muhammad Abdulrasheed a, 1 , Alexis Nzila b, c , Musa M. Musa a, d, * a Department of Chemistry, King Fahd University of Petroleum and Minerals, Dhahran 31261, Saudi Arabia b Department of Bioengineering, King Fahd University of Petroleum and Minerals, Dhahran 31261, Saudi Arabia c Interdisciplinary Research Center for Membranes and Water Security, King Fahd University of Petroleum and Minerals, Dhahran 31261, Saudi Arabia d Interdisciplinary Research Center for Refning and Advanced Chemicals, King Fahd University of Petroleum and Minerals, Dhahran 31261, Saudi Arabia A R T I C L E INFO Keywords: Alcohol dehydrogenases Asymmetric reduction Biocatalysis Enantiopure alcohols Bulky-bulky ketones ABSTRACT Biocatalytic asymmetric reduction of prochiral bulky-bulky ketones is an attractive approach to produce their corresponding valuable enantiopure alcohols. These ketones contain alkyl or aryl groups that exhibit subtle differences in size, and thus their asymmetric reduction is challenging. Bulky-bulky ketones include acyclic ketones that comprise an aryl ring in each side of the ketone or aryl and another relatively bulky group such as cyclohexyl or long chains; they also include prochiral cyclic ketones that comprise two moieties that are similar in their sizes such as tetralones and tetrahydrofuran-3-one. This review summarizes recent examples of bio- catalytic asymmetric reduction of bulky-bulky ketones, a transformation that is not easily accomplished not only by enzymes, but also by organo- and organometallic catalysis. Moreover, it has identifed gaps that limits the effciency of the biocatalytic asymmetric reduction of bulky-bulky ketones, and has proposed various strategies to improve this effciency. 1. Introduction Catalytic asymmetric reduction of ketones is a straightforward approach to obtaining optically active secondary alcohols [1–4]. Asymmetric reduction of bulky-bulky ketones, which comprise two groups that exhibit similar sizes, is among the challenging tasks because of the fact that the catalyst has to discern between two groups that slightly vary in their sizes. Although examples of asymmetric transfer hydrogenation of these substrates using transition metals have been reported [5,6], biocatalytic asymmetric reduction using ketoreductases (KREDs)/alcohol dehydrogenases (ADHs) remains an attractive approach [7–9], apparently because biocatalytic reactions are con- ducted under mild reaction conditions, which minimizes the formation of by-products [10–12]. Moreover, transition metal-based catalysts are expensive and tedious to prepare. Although enzymes seem to have po- tentials as green catalysts, however, the environmental aspects of the use of enzymes in chemical transformations have to be assessed based on the reaction burden on the environment (i.e., the E factor) [13–15]. Prochiral bulky-bulky ketones include substrates that contain two bulky substituents such as two aryl groups or aryl and a large alkyl group and the prochiral carbonyl is not within a cycle, referred to as acyclic bulky-bulky ketones throughout this article. They also include small cyclic ketones, which contain two substituents that are almost spatially symmetrical such as tetralones and tetrahydrofuran-3-one. Optically active alcohols produced via asymmetric reduction of these bulky-bulky ketones are important building blocks in pharmaceutically relevant compounds (Fig. 1). Alcohol dehydrogenases (EC 1.1.1.X, ADHs with X = 1, 2, or 252 will be discussed in this review) are an important class of enzymes that catalyze the interconversion of ketones and their corresponding opti- cally active secondary alcohols [27–31]. They require either nicotinamide-adenine dinucleotide (NAD + ) or its phosphate (NADP + ) as a cofactor. ADHs in general have a high substrate specifcity (i.e., limited substrate scope). The progression in the biotechnology feld using site-directed mutagenesis and directed evolution along with molecular dynamics simulations provided engineered mutants of ADHs that helped in widening their substrate specifcity to accept substrates that are not accepted by wild-type ADHs. This review summarizes recent examples of biocatalytic asymmetric reduction of prochiral bulky-bulky ketones using whole cells or purifed enzymes. * Corresponding author. E-mail address: musam@kfupm.edu.sa (M.M. Musa). 1 These Authors contributed equally Contents lists available at ScienceDirect Molecular Catalysis journal homepage: www.journals.elsevier.com/molecular-catalysis https://doi.org/10.1016/j.mcat.2023.113099 Received 30 December 2022; Received in revised form 26 February 2023; Accepted 18 March 2023