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.

中文翻译：

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千克级对映体纯 3,4-二取代四氢呋喃衍生物的化学和生化方法：KRED 的力量


报道了 （3S，4S）-4-甲基四氢呋喃-3-醇的可扩展合成，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使用低产率的酮三步合成法生产的，被认为不适用于未来的批次。寻找可扩展的环保工艺：一种生态设计方法导致酮的一步、高度对映和非对映选择性生物催化还原为目标中间体 （3S，4 S）-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，从而允许酮底物完全转化为所需的对映异构体。新路线导致所有关键绩效指标的显著改善，包括 PMI、溶剂和废物。