Enzymatic Primary Amination of Benzylic and Allylic C(sp3)-H Bonds
Enzymatic Primary Amination of Benzylic and Allylic C(sp3)-H Bonds
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DOI：
10.1021/jacs.0c03428
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发表时间：
2020-06-10
影响因子：
15
通讯作者：
Arnold, Frances H.
中科院分区：
文献类型：
--
作者：
Jia, Zhi-Jun;Gao, Shilong;Arnold, Frances H.
脂肪族伯胺广泛存在于天然产品、药品和功能材料中。虽然有太多的合成方法被报道，但直接在C(sp(3))-H键上安装游离胺基团的方法仍然是前所未有的。在这里，我们报告了一组新的自然酶，它们催化C(sp(3))-H键的直接伯胺化反应，具有很好的化学、区域和对映体选择性，使用容易获得的羟胺衍生物作为氮源。基因编码的细胞色素P411酶(P450的半胱氨酸对血红素铁的轴向配体已被Ser取代)的定向进化产生了选择性地使苄基和烯丙基C-H键功能化的变体，提供了广泛的对映体富集伯胺。这种生物催化过程是有效的和选择性的(高达3930TTN和96%ee)，并且可以在制备规模上进行。
Aliphatic primary amines are prevalent in natural products, pharmaceuticals, and functional materials. While a plethora of processes are reported for their synthesis, methods that directly install a free amine group into C(sp(3))-H bonds remain unprecedented. Here, we report a set of new-to-nature enzymes that catalyze the direct primary amination of C(sp(3))-H bonds with excellent chemo-, regio-, and enantioselectivity, using a readily available hydroxylamine derivative as the nitrogen source. Directed evolution of genetically encoded cytochrome P411 enzymes (P450s whose Cys axial ligand to the heme iron has been replaced with Ser) generated variants that selectively functionalize benzylic and allylic C-H bonds, affording a broad scope of enantioenriched primary amines. This biocatalytic process is efficient and selective (up to 3930 TTN and 96% ee), and can be performed on preparative scale.