Chemical and Biochemical Approaches to an Enantiomerically Pure 3,4-Disubstituted Tetrahydrofuran Derivative at a Multikilogram Scale: The Power of KRED

A scalable synthesis of (3S,4S)-4-methyltetrahydrofuran-3-ol involving a keto reductase-mediated enantio- and diastereoselective reduction of a racemic ketone substrate is reported. This chiral intermediate was initially produced using a low-yielding three-step synthesis from ketone, deemed not usab...

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Bibliographic Details
Published in:Organic process research & development 2024-12, Vol.28 (12), p.4467-4476
Main Authors: Bigot, Antony, Rabion, Alain, Landier, Jean-Bernard, Laronze, Geoffrey, Petit, Frédéric, Deprets, Stéphanie, Michot, Jean-Marc, Yuan, Changxia, Sun, Fenglai, Chen, Han, Hou, Longlei, Tang, Dalin
Format: Article
Language:English
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Summary:A scalable synthesis of (3S,4S)-4-methyltetrahydrofuran-3-ol involving a keto reductase-mediated enantio- and diastereoselective reduction of a racemic ketone substrate is reported. This chiral intermediate was initially produced using a low-yielding three-step synthesis from ketone, deemed not usable for future batches. Looking for a scalable and environmental process: an eco-design approach led to a one-step, highly enantio- and diastereoselective biocatalytic reduction of the ketone to the targeted intermediate (3S,4S)-4-methyltetrahydrofuran-3-ol. In addition, the reaction operates via dynamic kinetic resolution under unprecedented mild conditions of temperature and pH, allowing for a full conversion of the ketone substrate into the desired enantiomer. The new route led to a significant improvement of all the key performance indicators, including PMI, solvent, and waste.
ISSN:1083-6160
1520-586X
DOI:10.1021/acs.oprd.4c00388