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

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2024-11-14 DOI:10.1021/acs.oprd.4c0038810.1021/acs.oprd.4c00388

Antony Bigot*, Alain Rabion*, Jean-Bernard Landier, Geoffrey Laronze, Frédéric Petit, Stéphanie Deprets, Jean-Marc Michot, Changxia Yuan, Fenglai Sun, Han Chen, Longlei Hou and Dalin Tang,

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Abstract

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.

Abstract Image

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在多千克尺度上对映体纯3,4-二取代四氢呋喃衍生物的化学和生化方法：KRED的功率

报道了一种可扩展合成(3S,4S)-4-甲基四氢呋喃-3-醇的方法，该方法涉及酮还原酶介导的外消旋酮底物的对映和非对映选择性还原。这种手性中间体最初是用低产率的三步合成酮生产的，被认为不能用于未来的批次。寻找一种可扩展且环保的过程：一种生态设计方法导致了酮的一步，高度对映和非对映选择性生物催化还原为目标中间体(3S,4S)-4-甲基四氢呋喃-3-醇。此外，该反应在前所未有的温和温度和pH条件下通过动态动力学分辨率进行，允许酮底物完全转化为所需的对映体。新路线导致了所有关键绩效指标的显著改善，包括PMI、溶剂和浪费。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Organic Process Research & Development 化学-应用化学

CiteScore

6.90

自引率

14.70%

发文量

251

审稿时长

2 months

期刊介绍： The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools，process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.