Department of Chemistry, Indiana University, Bloomington, IN, 47405, USA.
Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, 60637, USA.
Angew Chem Int Ed Engl. 2021 Oct 25;60(44):23672-23677. doi: 10.1002/anie.202107982. Epub 2021 Aug 20.
Artificial metalloenzymes (ArMs) are commonly used to control the stereoselectivity of catalytic reactions, but controlling chemoselectivity remains challenging. In this study, we engineer a dirhodium ArM to catalyze diazo cross-coupling to form an alkene that, in a one-pot cascade reaction, is reduced to an alkane with high enantioselectivity (typically >99 % ee) by an alkene reductase. The numerous protein and small molecule components required for the cascade reaction had minimal effect on ArM catalysis. Directed evolution of the ArM led to improved yields and E/Z selectivities for a variety of substrates, which translated to cascade reaction yields. MD simulations of ArM variants were used to understand the structural role of the cofactor on ArM conformational dynamics. These results highlight the ability of ArMs to control both catalyst stereoselectivity and chemoselectivity to enable reactions in complex media that would otherwise lead to undesired side reactions.
人工金属酶 (ArMs) 常用于控制催化反应的立体选择性，但控制化学选择性仍然具有挑战性。在这项研究中，我们设计了一种二钌 ArM 来催化重氮交叉偶联形成烯烃，然后在一锅级联反应中，通过烯烃还原酶将其还原为具有高对映选择性的烷烃（通常 >99%ee）。级联反应所需的大量蛋白质和小分子成分对 ArM 催化的影响很小。ArM 的定向进化提高了各种底物的产率和 E/Z 选择性，从而转化为级联反应产率。对 ArM 变体的 MD 模拟用于理解辅因子对 ArM 构象动力学的结构作用。这些结果突出了 ArMs 控制催化剂立体选择性和化学选择性的能力，从而能够在复杂介质中进行反应，否则这些反应会导致不希望的副反应。
