Programmable late-stage C-H bond functionalization enabled by integration of enzymes with chemocatalysis
Programmable late-stage C-H bond functionalization enabled by integration of enzymes with chemocatalysis
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DOI：
10.1038/s41929-021-00603-3
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发表时间：
2021-04-29
期刊：
影响因子：
37.8
通讯作者：
Micklefield, Jason
中科院分区：
文献类型：
--
作者：
Craven, Elliott J.;Latham, Jonathan;Micklefield, Jason
新的化学和生物催化方法对未来可持续合成必需分子具有重要意义。过渡金属催化使一些复杂分子支架的后期C-H功能化成为可能，为有价值的产物提供了快速的途径，尽管这在很大程度上取决于选择性金属化的电子或立体倾向的C-H键的可用性，使某些区域选择性无法获得。与金属化学催化不同，酶可以催化C-H键功能化，区分几乎相同的非活化C-H键，提供具有精细区域选择性的产物。然而，酶通常提供比更多样化的化学催化更少的功能。在这里，我们报告了可编程的、区域选择性的C-H键功能化方法，通过将卤代酶与钯催化的氰化结合，随后将腈水合酶或腈酶结合，用于安装通用的腈、酰胺和羧酸基团。使用两组分或三组分化学生物催化系统，包括药物在内的复杂靶分子的区域选择性合成可以在一锅过程中实现，可在克尺度上操作。
New chemo- and biocatalytic methodology is important for the future sustainable synthesis of essential molecules. Transition metal catalysis enables the late-stage C-H functionalization of some complex molecular scaffolds, providing rapid routes to valuable products, although this is largely dependent on the availability of electronically or sterically predisposed C-H bonds for selective metalation, leaving certain regioselectivities inaccessible. Unlike metal chemocatalysis, enzymes can catalyse C-H bond functionalization, discriminating between near-identical, non-activated C-H bonds, delivering products with exquisite regioselectivity. However, enzymes typically provide access to fewer functionalities than more divergent chemocatalysis. Here we report programmable, regioselective C-H bond functionalization methodologies for the installation of versatile nitrile, amide and carboxylic acid moieties through integration of halogenase enzymes with palladium-catalysed cyanation and subsequent incorporation of nitrile hydratase or nitrilase enzymes. Using two- or three-component chemobiocatalytic systems, the regioselective synthesis of complex target molecules, including pharmaceuticals, can be achieved in a one-pot process operable on a gram scale.