Highly Efficient Production of Optically Active (R)-Tetrahydrothiophene-3-ol in Batch and Continuous Flow by Using Immobilized Ketoreductase,Organic Process Research & Development

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Highly Efficient Production of Optically Active (R)-Tetrahydrothiophene-3-ol in Batch and Continuous Flow by Using Immobilized Ketoreductase
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2022-02-15 , DOI: 10.1021/acs.oprd.1c00383
Vyasa Williams ₁ , Yuxia Cui ₁ , Jiadong Zhao ₁ , Han Fu ₁ , Xuecheng Jiao ₁ , Yulei Ma ₁ , Xiang Li ₁ , Xin Du ₁ , Na Zhang ₁

Affiliation

In this work, an engineered ketoreductase, apKRED-9, derived from Acetobacter pasteurianus 386B was successfully immobilized on two platforms, namely, glutaraldehyde-activated amino polymer beads, LX1000 HA, and cofactor enriched poly(ethylenimine) (CEP) mediated coaggregation followed by glutaraldehyde cross-linking, respectively. The enzyme apKRED-9 immobilized on LX1000HA was evaluated in a packed bed reactor (PBR) for continuous-flow synthesis of (R)-tetrahydrothiophene-3-ol from 3-keto tetrahydrothiophene in an aqueous-isopropanol mixture, while the enzyme apKRED-9 immobilized on CEP was tested in batch mode until pilot scale for the same reaction. The long-term operational stability of the enzyme in both continuous-flow and batch modes was demonstrated, with high conversion of >99.0% and ee > 99.5% in both the cases. From the pilot-scale application of apKRED-9-CEP, (R)-tetrahydrothiophene-3-ol was obtained (118.0 g, GC purity 99.9%, chiral purity ee 99.9% and yield 76.3%). In the PBR flow reactor, the productivity in terms of space time yield (STY) 729 g L^–1 d^–1 was achieved with 64 h of continuous usage. Based on performance metrics, both platforms are scalable and reproducible, while CEP offers additional advantages on effective cost and adaptability to other enzymes.

中文翻译：

使用固定化酮还原酶高效生产光学活性 (R)-四氢噻吩-3-醇

在这项工作中，一种源自巴氏醋杆菌 386B的工程酮还原酶ap KRED-9成功地固定在两个平台上，即戊二醛活化的氨基聚合物珠 LX1000 HA 和辅因子富集的聚（乙烯亚胺）（CEP）介导的共聚集。分别通过戊二醛交联。固定在 LX1000HA 上的酶ap KRED-9 在填充床反应器 (PBR) 中进行了评估，用于在水-异丙醇混合物中从 3-酮基四氢噻吩连续流动合成 ( R )-四氢噻吩-3-醇，而酶ap以分批模式测试固定在 CEP 上的 KRED-9，直到相同反应的中试规模。证明了酶在连续流动和分批模式下的长期操作稳定性，在两种情况下都具有 > 99.0% 和 ee > 99.5% 的高转化率。通过ap KRED-9-CEP的中试应用，得到( R )-四氢噻吩-3-醇（118.0 g，GC纯度99.9%，手性纯度ee 99.9%，收率76.3%）。在 PBR 流动反应器中，在时空产率 (STY) 方面的生产率为 729 g L ^–1 d ^–1，连续使用 64 小时。基于性能指标，这两个平台都具有可扩展性和可重复性，而 CEP 在有效成本和对其他酶的适应性方面提供了额外的优势。

更新日期：2022-02-15

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