An enzymatic platform for the asymmetric amination of primary, secondary and tertiary C(sp3)–H bonds
An enzymatic platform for the asymmetric amination of primary, secondary and tertiary C(sp3)–H bonds
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DOI：
10.1038/s41557-019-0343-5
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发表时间：
2019-10
期刊：
影响因子：
21.8
通讯作者：
Yang Yang-Yang;I. Cho;X. Qi;Peng Liu;F. Arnold
中科院分区：
文献类型：
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作者：
Yang Yang-Yang;I. Cho;X. Qi;Peng Liu;F. Arnold
选择性官能化无处不在的C-H键的能力简化了从容易获得的前体构建复杂分子结构的过程。在这里，我们报告酶催化剂来自细胞色素P450，使用氮烯转移机制的对映选择性胺化的初级，二级和三级C（sp3）-H键。这些完全遗传编码的酶在细菌中产生并发挥作用，在细菌中它们可以通过定向进化进行优化，用于广谱的对映选择性C（sp3）-H胺化反应。这些催化剂可以胺化多种苄基、烯丙基和脂肪族C-H键，对映体选择性好，产物可以选择对映体。对映体选择性胺化的主要C（sp3）-H键在基板上，承担偕二甲基取代基提供手性胺，具有季立体中心。此外，这些酶使具有叔C（sp3）-H键的外消旋底物的对映体会聚转化，以提供具有四取代的立体中心的产物，这是一个逃避小分子催化剂的过程。进一步的工程允许甲基-乙基立体中心的对映选择性构建，这在不对称催化中是众所周知的挑战。
The ability to selectively functionalize ubiquitous C–H bonds streamlines the construction of complex molecular architectures from easily available precursors. Here we report enzyme catalysts derived from a cytochrome P450 that use a nitrene transfer mechanism for the enantioselective amination of primary, secondary and tertiary C(sp3)–H bonds. These fully genetically encoded enzymes are produced and function in bacteria, where they can be optimized by directed evolution for a broad spectrum of enantioselective C(sp3)–H amination reactions. These catalysts can aminate a variety of benzylic, allylic and aliphatic C–H bonds in excellent enantioselectivity with access to either antipode of product. Enantioselective amination of primary C(sp3)–H bonds in substrates that bear geminal dimethyl substituents furnished chiral amines that feature a quaternary stereocentre. Moreover, these enzymes enabled the enantioconvergent transformation of racemic substrates that possess a tertiary C(sp3)–H bond to afford products that bear a tetrasubstituted stereocentre, a process that has eluded small-molecule catalysts. Further engineering allowed for the enantioselective construction of methyl–ethyl stereocentres, which is notoriously challenging in asymmetric catalysis.