Biocatalytic asymmetric reduction of prochiral bulky-bulky ketones

Sardauna, Auwal Eshi; Abdulrasheed, Muhammad; Nzila, Alexis; Musa, Musa

doi:10.1016/j.mcat.2023.113099

Cited by 8 publications

(4 citation statements)

References 72 publications

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“…The challenging aspect of asymmetric reduction for ketones with large, similar-sized groups lies in the need for the catalyst to differentiate between two groups that have subtle size differences. [19,24] Table 2 summarizes the obtained results, again both in terms of substrates conversion and ee of the obtained product.…”

Section: Hsdhs Screening For the Stereoselective Reduction Of Symmetr...mentioning

confidence: 99%

Promiscuity and Selectivity of Hydroxysteroid Dehydrogenases in the Biocatalyzed Reduction of 1,2‐Diketones

Tognoli,

Bertuletti,

Patti

et al. 2023

ChemCatChem

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Hydroxysteroid dehydrogenases (HSDHs) are NAD(P)H‐dependent alcohol dehydrogenases (ADHs) known for their exceptional stereo‐ and regioselectivity when acting on natural substrates, including neutral steroids, bile acids, and various steroid derivatives. Notably, in recent studies this specific subfamily of oxidoreductases has displayed intriguing substrate promiscuity, exhibiting the capacity to accommodate a diverse array of substrates, such as sterically hindered ketones and even α‐keto esters. Herein, we further explored the promiscuous nature of HSDHs by investigating their catalytic activity with representative 1,2‐diketones. This set encompasses symmetric aliphatic/aromatic diketones — namely, 3,4‐hexandione and benzil — as well as the asymmetric synthon 1‐phenyl‐1,2‐propanedione. In the case of 3,4‐hexandione, substrate conversion and selectivity closely resembled that previously observed with aliphatic α‐keto esters. On the contrary, a more heterogeneous behavior was observed in the case of aromatic substrates, with diverse performances in terms of conversions and stereo‐ or regioselectivity. Additionally, docking studies were carried out to get a deeper insight in the stereochemistry of 1,2‐diketones reduction catalyzed by the broad substrate scope and steroid‐active ketoreductase Is2‐SDR.

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Section: Hsdhs Screening For the Stereoselective Reduction Of Symmetr...mentioning

confidence: 99%

Promiscuity and Selectivity of Hydroxysteroid Dehydrogenases in the Biocatalyzed Reduction of 1,2‐Diketones

Tognoli,

Bertuletti,

Patti

et al. 2023

ChemCatChem

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“…33,34 The bioreduction of bulky and sterically demanding substrates is challenging and has been addressed by whole cell biocatalysis. 35 Recently, the bacterial whole cell reduction of sterically hindered 3,5-dioxo-5-phenylpentanoate (1) was reported by Żądło-Dobrowolska et al (Scheme 1). 36 The authors screened several species and identified stereocomplementary bacterial strains that could yield both enantiomers of 3-hydroxy-5-oxo-5-phenylpentanoates (2) and 5-hydroxy-3-oxo-5-phenylpentanoates (3).…”

Section: Bacterial Strains In Redox Biotransformationsmentioning

confidence: 99%

“…Some recent reviews have updated the application of ketoreductases in asymmetric synthesis. [15][16][17]35,105 Li et al described the use of ketoreductases including engineered enzymes that were reported between 2018 and 2020, in the asymmetric synthesis of pharmaceuticals. 15 Another recent review elaborated on the use of wild type and engineered anti-Prelog ADHs in the synthesis of optically active alcohols.…”

Section: Protein Engineering Of Carbonyl Reductasesmentioning

confidence: 99%

Microbial alcohol dehydrogenases: recent developments and applications in asymmetric synthesis

Chadha,

Padhi,

Stella

et al. 2024

Org. Biomol. Chem.

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“…For instance, ( S )-2-chloro-1-(2′,4′-dichlorophenyl)ethanol is essential in the synthesis of ticonazole, a treatment for vaginal candidiasis and superficial fungal infections of the skin. , Similarly, ( R )-2-chloro-1-phenylethanol is used in the synthesis of mirabegron, a β-3 adrenergic receptor agonist, and ( S )-2-chloro-1-(3,4-difluorophenyl)ethanol is used in the synthesis of ticagrelor, a receptor antagonist . Optically active alcohols are typically obtained through asymmetric reduction of prochiral ketones , or via kinetic resolution (KR) or deracemization of racemates. , However, KR is limited to 50% yield with high enantiopurity, while deracemization necessitates multiple catalysts with specific stereopreferences operating in the same vessel, hampering the development of new deracemization approaches. Consequently, the asymmetric reduction of prochiral 2-haloacetophenones presents a straightforward option for producing enantiopure 2-halo-1-arylethanols.…”

Section: Introductionmentioning

confidence: 99%

Enantiocomplementary Asymmetric Reduction of 2–Haloacetophenones Using TeSADH: Synthesis of Enantiopure 2-Halo-1-arylethanols

Abdulrasheed,

Sardauna,

Alhaffar

et al. 2024

ACS Omega

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Enantiopure 2-halo-1-arylethanols are essential precursors for the synthesis of pharmaceuticals, agrochemicals, and fine chemicals. This study investigates the asymmetric reduction of 2-haloacetophenones and their substituted analogs to obtain their corresponding optically active 2-halo-1-arylethanols using secondary alcohol dehydrogenase from Thermoanaerobacter pseudethanolicus (TeSADH) mutants. Specifically, the ΔP84/A85G and P84S/A85G TeSADH mutants were evaluated for the asymmetric reduction of 2-haloacetophenones, generating their corresponding optically active halohydrins with high enantioselectivities. The asymmetric reduction of 2-haloacetophenones and their substituted analogs using the ΔP84/A85G TeSADH mutant yielded their corresponding (S)-2-halo-1-arylethanols with high enantiopurity in accordance with the anti-Prelog's rule. Conversely, the P84S/A85G TeSADH mutant produced (R)-alcohols when reducing 2-chloro-4′-chloroacetophenone, 2chloro-4′-bromoacetophenone, and 2-bromo-4′-chloroacetophenone, while generating the (S)-configured halohydrin from 2-chloro-4′-fluoroacetophenone. Asymmetric reduction of the unsubstituted 2-bromoacetophenone, 2-chloroacetophenone, and 2,2,2trifluoroacetophenone resulted in production of their (S)-halohydrins with the tested mutants, which reflects the importance of the nature of the substituent on the substrate's ring in controlling the stereopreference of these TeSADH-catalyzed reduction reactions. These findings contribute to the understanding and application of TeSADH in synthesizing optically active compounds and aid in the design of further mutants with the desired stereopreference.

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Biocatalytic asymmetric reduction of prochiral bulky-bulky ketones

Cited by 8 publications

References 72 publications

Promiscuity and Selectivity of Hydroxysteroid Dehydrogenases in the Biocatalyzed Reduction of 1,2‐Diketones

Promiscuity and Selectivity of Hydroxysteroid Dehydrogenases in the Biocatalyzed Reduction of 1,2‐Diketones

Microbial alcohol dehydrogenases: recent developments and applications in asymmetric synthesis

Enantiocomplementary Asymmetric Reduction of 2–Haloacetophenones Using TeSADH: Synthesis of Enantiopure 2-Halo-1-arylethanols

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