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Enantioselective Synthesis of Pharmaceutically Relevant Bulky Arylbutylamines Using Engineered Transaminases

Sheludko, Yuriy V. ; Slagman, Sjoerd ; Gittings, Samantha ; Charnock, Simon J. ; Land, Henrik ; Berglund, Per ; Fessner, Wolf‐Dieter (2022)
Enantioselective Synthesis of Pharmaceutically Relevant Bulky Arylbutylamines Using Engineered Transaminases.
In: Advanced Synthesis & Catalysis, 2022, 364 (17)
doi: 10.26083/tuprints-00022896
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Item Type: Article
Type of entry: Secondary publication
Title: Enantioselective Synthesis of Pharmaceutically Relevant Bulky Arylbutylamines Using Engineered Transaminases
Language: English
Date: 23 December 2022
Place of Publication: Darmstadt
Year of primary publication: 2022
Publisher: Wiley-VCH
Journal or Publication Title: Advanced Synthesis & Catalysis
Volume of the journal: 364
Issue Number: 17
DOI: 10.26083/tuprints-00022896
Corresponding Links:
Origin: Secondary publication DeepGreen
Abstract:

ATAs engineered for having an enlarged small binding pocket were applied for the synthesis of enantiomerically pure (R)‐benzo[1,3]dioxol‐5‐yl‐butylamine, a chiral component of human leukocyte elastase inhibitor DMP 777 (L‐694,458). Kinetic resolution of the racemic amine was performed by using the L59A variant of the (S)‐selective ATA from Chromobacterium violaceum (Cv‐ATA), providing the residual (R)‐enantiomer in excellent yield and >99% ee. At moderate enzyme loading and absence of co‐solvent, high volumetric productivity of 0.22 mol L⁻¹ h⁻¹ (42.5 g L⁻¹ h⁻¹) was achieved. Complementarily, the (S)‐enantiomer was generated via kinetic resolution using the (R)‐selective ATA‐117‐Rd11 from Arthrobacter sp. with acetone as the amino acceptor. In an alternative approach, we employed ATA‐117‐Rd11 for the asymmetric amination of the prochiral ketone precursor, which at 86% conversion gave the (R)‐benzo[1,3]dioxol‐5‐yl‐butylamine with excellent >99% ee. We further evaluated the utility of Cv‐ATA L59A for the asymmetric synthesis of pharmaceutically relevant (S)‐1‐phenylbutan‐1‐amine, a chiral component of the deubiquitinase inhibitor degrasyn (WP1130). The enzyme showed good tolerance to high concentrations of isopropylamine, producing (S)‐1‐phenylbutan‐1‐amine in enantiomerically pure form (>99% ee).

Uncontrolled Keywords: Aminotransferase, Biocatalysis, Chiral amines, Kinetic resolution, Protein engineering
Status: Publisher's Version
URN: urn:nbn:de:tuda-tuprints-228969
Classification DDC: 500 Science and mathematics > 540 Chemistry
Divisions: 07 Department of Chemistry > Clemens-Schöpf-Institut > Organ Chemistry
Date Deposited: 23 Dec 2022 13:28
Last Modified: 14 Nov 2023 19:05
SWORD Depositor: Deep Green
URI: https://tuprints.ulb.tu-darmstadt.de/id/eprint/22896
PPN: 503266280
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