Chemoenzymatic conversion of amides to enantioenriched alcohols in aqueous medium
Chemoenzymatic conversion of amides to enantioenriched alcohols in aqueous medium
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DOI：
10.1038/s42004-019-0182-8
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发表时间：
2019-07-19
影响因子：
5.9
通讯作者：
Garg, Neil K.
中科院分区：
文献类型：
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作者：
Dander, Jacob E.;Giroud, Maude;Garg, Neil K.
结合联合收割机非酶和生物催化转化的一锅反应代表了化学合成中的新兴策略。一些最强大的化学酶促方法，虽然不常见，是那些在反应碳之一形成碳-碳（C-C）键和立构中心，从而简化传统的逆合成断开。在这里，我们报告的一锅，化学酶转化酰胺对映体富集醇。这种转化结合了镍催化的Suzuki-Miyaura偶联酰胺在水介质中的不对称，生物催化还原，以提供高产率和对映体过量的二芳基甲醇衍生物。该平台的合成效用通过药物orphenadrine的两个对映体的正式合成来强调，其依赖于灌输互补立体选择性的酮还原酶。我们提供了一个解释的立体选择性的基础上分析的酶结合口袋的起源。
One-pot reactions that combine non-enzymatic and biocatalytic transformations represent an emerging strategy in chemical synthesis. Some of the most powerful chemoenzymatic methodologies, although uncommon, are those that form a carbon-carbon (C-C) bond and a stereocenter at one of the reacting carbons, thereby streamlining traditional retrosynthetic disconnections. Here we report the one-pot, chemoenzymatic conversion of amides to enantioenriched alcohols. This transformation combines a nickel-catalyzed Suzuki-Miyaura coupling of amides in aqueous medium with an asymmetric, biocatalytic reduction to provide diarylmethanol derivatives in high yields and enantiomeric excesses. The synthetic utility of this platform is underscored by the formal syntheses of both antipodes of the pharmaceutical orphenadrine, which rely on ketoreductase enzymes that instill complementary stereoselectivities. We provide an explanation for the origins of stereoselectivity based on an analysis of the enzyme binding pockets.