用于 Hajos-Parrish/Wieland-Miescher 酮的动力学拆分和级联还原的烯还原酶的发现和工程,Advanced Synthesis & Catalysis

当前位置： X-MOL 学术 › Adv. Synth. Catal. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

用于 Hajos-Parrish/Wieland-Miescher 酮的动力学拆分和级联还原的烯还原酶的发现和工程
Advanced Synthesis & Catalysis ( IF 4.4 ) Pub Date : 2023-06-02 , DOI: 10.1002/adsc.202300326
Dongyan Li ₁ , He Dong ₁ , Xianwen Chen ₂ , Yangyang Li ₂ , Yiping Xu ₂ , Jing Wang ₂ , Jiali Fang ₂ , Chenming Huang ₂ , Wenhe Zhang ₂ , Xian Jia ₂ , Song You ₂ , Bin Qin ₂

Affiliation

烯还原酶（ERED）催化α,β-不饱和酮的不对称还原是有机合成中一种有吸引力的方法。通过 BsER（来自枯草芽孢杆菌的 ERED）的发现和进一步的结构引导蛋白质工程，对著名的构建模块 Hajos-Parrish 酮 (HPK, 1 a ) 和 Wieland-Miescher 酮 (WMK, 1 ) 进行选择性生物还原b ) 在本研究中取得了成果。光学纯的 ( R ) - HPK (( R )- 1 a ) 和 ( R ) - WMK (( R )- 1 b ) 具有相应的 >99% 和 98% 对映体过量 ( ee) 值是通过外消旋底物的动力学拆分获得的。据我们所知，这是 ERED 介导的rac -HPK 和rac -WMK 动力学拆分的第一个例子。此外，还原产物顺式-7a-甲基六氢-1H-茚-1,5(4H)-二酮( cis - 2a )和顺式-8a-甲基六氢萘-1,6(2H,5H)-二酮(还获得了具有高非对映体比率( dr )的cis - 2b )。我们还开发了涉及 BsER 和酮还原酶 (KRED) 的四种生物催化级联还原途径。使用优化的 ERED-KRED 和 KRED-ERED 级联，( S ) -HPK (( S )- 1 a ) 和 ( S ) - WMK (( S )- 1 b ) 可以逐步还原，产生纯度 >91% 的生物活性产物。本研究提出了 HPK 和 WMK 的动力学拆分和级联还原的生物催化策略（1a和1b）。

"点击查看英文标题和摘要"

Discovery and Engineering of an Ene-reductase for Kinetic Resolution and Cascade Reduction of Hajos-Parrish/Wieland-Miescher Ketones

Ene-reductase (ERED)-catalyzed asymmetric reduction of α,β-unsaturated ketones is an attractive method in organic synthesis. Through the discovery and further structure-guided protein engineering of BsER, an ERED from Bacillus subtilis, the selective bio-reduction of the well-known building blocks Hajos-Parrish ketone (HPK, 1 a) and Wieland-Miescher ketone (WMK, 1 b) was achieved in this study. The optically pure (R)-HPK ((R)-1 a) and (R)-WMK ((R)-1 b) with corresponding >99% and 98% enantiomeric excess (ee) values were obtained by kinetic resolution of the racemic substrates. To the best of our knowledge, this is the first example of ERED mediated kinetic resolution of rac-HPK and rac-WMK. In addition, the reduction products cis-7a-methylhexahydro-1H-indene-1,5(4H)-dione (cis-2 a) and cis-8a-methylhexahydronaphtha- lene-1,6(2H,5H)-dione (cis-2 b) with high diastereomeric ratios (dr) were also obtained. We also developed four routes of biocatalytic cascade reduction involving BsER and ketoreductases (KREDs). Using optimized ERED-KRED and KRED-ERED cascades, (S)-HPK ((S)-1 a) and (S)-WMK ((S)-1 b) could be reduced stepwise, yielding the bioactive products all with >91% purity. This study presents a biocatalytic strategy for the kinetic resolution and cascade reduction of HPK and WMK (1 a and 1 b).

更新日期：2023-06-02

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南