Substituent Position‐Controlled Stereoselectivity in Enzymatic Reduction of Diaryl‐ and Aryl(heteroaryl)methanones

Li, Zhining; Wang, Zexu; Wang, Yuhan; Wu, Xiaofan; Lü, Hong; Huang, Zedu; Chen, Fen‐Er

doi:10.1002/adsc.201801543

Cited by 19 publications

(24 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nevertheless, some useful enzymes have been reported comprising the ADHs from Sphingobium yanoikuyae (SyADH) (Lavandera et al, 2008a;Cuetos et al, 2012;Man et al, 2014), Ralstonia sp. (RasADH) (Lavandera et al, 2008a;Cuetos et al, 2012;Man et al, 2014), Sporobolomyces salmonicolor (SsADH) Li et al, 2009;Li et al, 2010;Chen et al, 2012) Kluyveromyces polysporus (KpADH) (Xu et al, 2018) Clostridium acetobutylicum (CaADH) (Applegate et al, 2011), hydroxysteroid dehydrogenases (Zhu et al, 2006a;Ferrandi et al, 2020) and enzymes from Kluyveromyces marxianus (Li et al, 2019) or Kluyveromyces polysporus (Xu et al, 2018;Zhou et al, 2020). A selection of bulky ketones reduced by ADHs is given in Figure 17.…”

Section: Adh-catalysed Reduction Reactionsmentioning

confidence: 99%

Alcohol Dehydrogenases as Catalysts in Organic Synthesis

2022

View full text Add to dashboard Cite

Alcohol dehydrogenases (ADHs) have become important catalysts for stereoselective oxidation and reduction reactions of alcohols, aldehydes and ketones. The aim of this contribution is to provide the reader with a timely update on the state-of-the-art of ADH-catalysis. Mechanistic basics are presented together with practical information about the use of ADHs. Current concepts of ADH engineering and ADH reactions are critically discussed. Finally, this contribution highlights some prominent examples and future-pointing concepts.

show abstract

Section: Adh-catalysed Reduction Reactionsmentioning

confidence: 99%

Alcohol Dehydrogenases as Catalysts in Organic Synthesis

2022

View full text Add to dashboard Cite

show abstract

“…Using Kp ADH as the template for genome mining, a new reductase named KmCR2 was discovered by our group from Kluyveromyces marxianus CBS4857 and it displayed a broad substrate spectrum towards the reduction of diaryl‐ and aryl(heteroaryl)methanones [42h] . During the study, the position of the substituent on aromatic rings ( meta versus para or ortho ) was revealed to control the stereospecificity of KmCR2.…”

Section: Creation Of One Stereocenter Through Kred‐catalyzed Reductionmentioning

confidence: 99%

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

Yang

Liu

et al. 2021

The Chemical Record

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…[ 7,8 ] Although it is extremely active to the aliphatic tert ‐butyl 6‐substituted (5 R / S )‐hydroxy‐3‐oxohexanoates, the activity and stability of Km AKR need to be improved since the economics of the catalyst, and it shows no activity to aromatic ketone so that its general application is limited. [ 12 ] Numerous enantiomerically pure aryl alcohols, such as aryl halohydrin, [ 13 ] diaryl‐ and aryl(heteroaryl)methanols, [ 14 ] are privileged structural elements in pharmaceutical molecules. Hence, it is of critical significance to expand the substrate scope of Km AKR by directed evolution.…”

Section: Introductionmentioning

confidence: 99%

Fluorescence‐based screening for engineered aldo‐keto reductase KmAKR with improved catalytic performance and extended substrate scope

Qiu

et al. 2021

Biotechnology Journal

View full text Add to dashboard Cite

Background Aldo‐keto reductases‐catalyzed transformations of ketones to chiral alcohols have become an established biocatalytic process step in the pharmaceutical industry. Previously, we have discovered an aldo‐keto reductase (AKR) from Kluyveromyces marxianus that is active to the aliphatic tert‐butyl 6‐substituted (5R/S)‐hydroxy‐3‐oxohexanoates, but it is inactive to aromatic ketones. In order to acquire an excellent KmAKRmutant for ensuring the simultaneous improvement of activity‐thermostability toward tert‐butyl 6‐cyano‐(5R)‐hydroxy‐3‐oxohexanoate ((5R)‐1) and broadening the universal application prospects toward more substrates covering both aliphatic and aromatic ketones, a fluorescence‐based high‐throughput (HT) screening technique was established. Main Methods and Major Results The directed evolution of KmAKR variant M5 (KmAKR‐W297H/Y296W/K29H/Y28A/T63M) produced the “best” variant M5‐Q213A/T23V. It exhibited enhanced activity‐thermostability toward (5R)‐1, improved activity toward all 18 test substrates and strict R‐stereoselectivity toward 10 substrates in comparison to M5. The enhancement of enzymatic activity and the extension of substrate scope covering aromatic ketones are proposed to be largely attributed to pushing the binding pocket of M5‐Q213A/T23V to the enzyme surface, decreasing the steric hindrance at the entrance and enhancing the flexibility of loops surrounding the active center. In addition, combined with 0.94 g dry cell weight (DCW) L−1 glucose dehydrogenase from Exiguobacterium sibiricum (EsGDH) for NADPH regeneration, 2.81 g DCW L−1 M5‐Q213A/T23V completely converted (5R)‐1 of up to 450 g L−1 at 120 g g–1 substrates/catalysts (S/C), yielding the corresponding optically pure tert‐butyl 6‐cyano‐(3R,5R)‐dihydroxyhexanoate ((3R,5R)‐2, > 99.5% d.e.p) with a space‐time yield (STY) of 1.08 kg L−1 day−1. Conclusions A fluorescence‐based HT screening system was developed to tailor KmAKR's activity, thermostability and substrate scope. The “best” variant M5‐Q213A/T23V holds great potential application for the synthesis of aliphatic/aromatic R‐configuration alcohols.

show abstract

Substituent Position‐Controlled Stereoselectivity in Enzymatic Reduction of Diaryl‐ and Aryl(heteroaryl)methanones

Cited by 19 publications

References 61 publications

Alcohol Dehydrogenases as Catalysts in Organic Synthesis

Alcohol Dehydrogenases as Catalysts in Organic Synthesis

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

Fluorescence‐based screening for engineered aldo‐keto reductase KmAKR with improved catalytic performance and extended substrate scope

Contact Info

Product

Resources

About