Efficient synthesis of an apremilast precursor and chiral β-hydroxy sulfones via ketoreductase-catalyzed asymmetric reduction,Organic & Biomolecular Chemistry

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Efficient synthesis of an apremilast precursor and chiral β-hydroxy sulfones via ketoreductase-catalyzed asymmetric reduction
Organic & Biomolecular Chemistry ( IF 2.9 ) Pub Date : 2022-02-14 , DOI: 10.1039/d1ob02485j
Jiyang Guo ₁ , Xiao Gao ₁ , Dong Qian ₁ , Huibin Wang ₁ , Xian Jia ₂ , Wenhe Zhang ₁ , Bin Qin ₃ , Song You ₁

Affiliation

Ketoreductase (KRED)-catalyzed asymmetric reduction of prochiral ketones is an attractive method to synthesize chiral alcohols. Herein, two KREDs LfSDR1-V186A/E141I and CgKR1-F92I with complementary stereopreference were identified towards reduction of apremilast prochiral ketone intermediate 1a. LfSDR1-V186A/E141I exhibited >99% conversion and 99.2% ee yielding an apremilast chiral alcohol intermediate ((R)-2a) at 50 g L⁻¹ substrate loading. Furthermore, we investigated the substrate scope of β-keto sulfones by using LfSDR1-V186A/E141I and CgKR1-F92I to produce both enantiomers of the corresponding β-hydroxy sulfones, with good-to-excellent conversion (up to >99%) and enantioselectivity (up to 99.9% ee) being obtained in most cases. Finally, the gram-scale synthesis of (R)-2a was performed by employing the crude enzyme of LfSDR1-V186A/E141I and BsGDH to afford the desired enantiomer with >99% conversion, 85.9% isolated yield and 99.2% ee. This study presents a biocatalytic strategy to synthesize chiral β-hydroxy sulfones.

中文翻译：

通过酮还原酶催化的不对称还原有效合成阿普斯特前体和手性β-羟基砜

酮还原酶（KRED）催化前手性酮的不对称还原是合成手性醇的一种有吸引力的方法。在此，鉴定出具有互补立体偏好的两个 KRED LfSDR1-V186A/E141I 和 CgKR1-F92I 用于还原阿普斯特前手性酮中间体1a 。 LfSDR1-V186A/E141I表现出>99%转化率和99.2% ee，在50 g L ^-1底物负载量下产生阿普斯特手性醇中间体(( R ) -2a )。此外，我们通过使用 LfSDR1-V186A/E141I 和 CgKR1-F92I 来研究 β-酮基砜的底物范围，以产生相应 β-羟基砜的两种对映体，具有良好到优异的转化率（高达 >99%）和大多数情况下可获得对映选择性（高达 99.9% ee）。最后，利用LfSDR1-V186A/E141I的粗酶和BsGDH进行克级合成( R ) -2a ，得到所需的对映体，转化率>99%，分离收率85.9%，ee 99.2%。本研究提出了合成手性 β-羟基砜的生物催化策略。

更新日期：2022-02-14

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