HHDH-Catalyzed Synthesis of Enantioenriched Fluorinated β-Hydroxy Nitrile─Process Advances through a Reaction Engineering Approach

Milčić, Nevena; Sudar, Martina; Marić, Ana-Katarina; Kos, Krešimir; Majerić Elenkov, Maja; Findrik Blažević, Zvjezdana (2024) HHDH-Catalyzed Synthesis of Enantioenriched Fluorinated β-Hydroxy Nitrile─Process Advances through a Reaction Engineering Approach. Industrial & Engineering Chemistry Research, 63 (16). pp. 7051-7063. ISSN 0888-5885

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Abstract

This study explores halohydrin dehalogenase (HHDH) variant ISM-4 for the synthesis of enantioenriched fluorinated β-hydroxy nitrile, focusing on the reaction engineering perspective for the enhancement of process metrics. Detailed kinetic assessments, enzyme affinities, inhibitions, and deactivation dependency are integrated into a mathematical model, providing insights into ISM-4 limitations and optimal conditions for (S)-3-(4-fluorophenyl)-3-hydroxypropanenitrile’s synthesis. By strategically feeding the substrate in a fed-batch or a repetitive-batch reactor, substantial improvements are achieved compared to the batch reactor, yielding the 75 and 145 mM desired product with ee > 90 and 80%, respectively. Additionally, findings from in silico simulations guided the selection of process conditions for a reaction on a 100 mL scale in a rotating-bed reactor with an immobilized catalyst, resulting in the 24.7 mM product (Y = 72%, ee 92%). This study highlights the important role of a reaction engineering approach in enhancing HHDH-catalyzed synthesis for scalable production of valuable enantioenriched building blocks.

Item Type:	Article
Uncontrolled Keywords:	biocatalysis; enantioselectivity; fluorinated chiral building blocks; halohydrin dehalogenase; hydroxy nitrile; kinetics; kinetic resolution; mathematical modelling
Subjects:	TECHNICAL SCIENCES > Chemical Engineering
Divisions:	Division of Organic Chemistry and Biochemistry
Projects:	Project title Project leader Project code Project type Enzimska sinteza fluoriranih kiralnih građevnih blokova-EnzyFluor Maja Majerić-Elenkov; Zvjezdana Findrik Blažević; Martina Sudar; Nevena Milčić IP-2018-01-4493 HRZZ
Depositing User:	Ema Buhin Šaler
Date Deposited:	24 Mar 2026 15:45
URI:	http://fulir.irb.hr/id/eprint/11453
DOI:	10.1021/acs.iecr.4c00477

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