Role of Engineered Iron-haem Enzyme in Reactivity and Stereoselectivity of Intermolecular Benzylic C-H Bond Amination
Role of Engineered Iron-haem Enzyme in Reactivity and Stereoselectivity of Intermolecular Benzylic C-H Bond Amination
复制标题
工程铁血红素酶在分子间苄基 C–H 键胺化反应活性和立体选择性中的作用
DOI：
10.1021/acscatal.0c00248
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发表时间：
2020-05-01
期刊：
影响因子：
12.9
通讯作者：
Gao, Yi Qin
中科院分区：
文献类型：
--
作者：
Wang, Juping;Gao, Hui;Gao, Yi Qin
最近的一项成功，其中工程铁血红素酶P411(CHA)‘胺化分子间的苄基C-H键，同时具有高效和立体选择性，解决了合成化学中的一个长期存在的挑战(Arnold和同事NAT。化学。2017年，9629-634)。本文通过量子力学(QM)/分子力学(MM)计算研究了该反应的反应机理、反应活性和立体选择性。为了更好地了解生物催化剂P411(CHA)‘如此优异的催化性能的来源，还从理论上比较了铁辅助因子FePIX单独用于分子间C-H键胺化反应的情况。催化循环包括两个过程：N-2解离和氮烯转移。计算结果表明，P411(CHA)‘酶催化分子间C-H胺化反应具有较高的反应活性和立体选择性，而FePIX催化的反应对N-2解离和氮转移的阻挡能力远高于P411(CHA)。P411(CHA)‘和FePIX的催化活性如此显著差异的原因是前者允许形成前驱体B-(5)Pr1和B-(3)Pr2，它们在结构上分别接近过渡态B-(3)TS1和B-(3)TS2，并加速N-2解离和氮转移。突变残基(A82L、A78V、F263L)通过有效地减小血红蛋白远端口袋的大小，促进B-(5)PR1和B-(3)PR2的形成。P411(CHA)的高立体选择性源于H-抽提中的空间效应。并对对位取代基R对反应活性的影响进行了理论分析。底物上含有较强的pI型给电子基，显著提高了P411(CHA)催化的分子间C-H胺化反应活性。这些结果为设计和构建具有高反应活性和立体选择性的环境友好的生物催化C-H胺化体系提供了有价值的信息。
A recent success in which the engineered iron-haem enzymes P411(CHA)' aminate the intermolecular benzylic C-H bond with both high efficiency and stereoselectivity solves a long-standing challenge in synthetic chemistry (Arnold and co-workers Nat. Chem. 2017, 9, 629-634). The mechanism, reactivity, and stereoselectivity of this reaction were studied by quantum mechanical (QM)/molecular mechanical (MM) calculations in this work. To understand better the origin of such an excellent catalytic performance of biocatalyst P411(CHA)', iron-cofactor FePIX alone for the intermolecular C-H bond amination was also theoretically investigated as a comparison. The catalytic cycle includes two processes: N-2 dissociation and nitrene transfer. The calculation results show that P411(CHA)' enzyme can catalyze intermolecular C-H amination with high reactivity and stereoselectivity, whereas the FePIX-catalyzed reaction has much higher barriers for both N-2 dissociation and nitrene transfer compared to P411(CHA)'. The reason for this dramatic difference in catalytic reactivity between P411(CHA)' and FePIX is that the former but not the latter allows the formation of precursors B-(5)PR1 and B-(3)PR2, which are structurally close to transition states B-(3)TS1 and B-(3)TS2 and accelerate N-2 dissociation and nitrene transfer, respectively. The mutated residues (A82L A78V F263L) assist the formations of B-(5)PR1 and B-(3)PR2 via reducing effectively the size of the haem distal pocket. High stereoselectivity of P411(CHA)' stems from the steric effect in H-abstraction. A theoretical analysis on how para substituent R affects reactivity was also carried out. A strong pi-type electron-donating group on the substrate enhances significantly the reactivity of P411(CHA)' -catalyzed intermolecular C-H amination. These results provide valuable information for designing and constructing environmentally friendly biocatalytic C-H amination systems with high reactivity and stereoselectivity.