Enantioconvergent Benzylic C(sp3)‒N Coupling With a Copper-Substituted Nonheme Enzyme
Document Type
Article
Author ORCID Identifier
Xuzhong Shen https://orcid.org/0000-0002-4779-3584
Jesse B. Brown https://orcid.org/0009-0001-9167-5462
James G. Zhang https://orcid.org/0000-0002-6802-7061
Xinyuan Ji https://orcid.org/0000-0002-8225-3663
Jinyan Rui https://orcid.org/0000-0002-8001-4458
Marc Garcia‐Borràs https://orcid.org/0000-0001-9458-1114
Yi Rao https://orcid.org/0000-0001-9882-1314
Yun‐Fang Yang https://orcid.org/0000-0002-6287-1640
Xiongyi Huang https://orcid.org/0000-0001-7156-8881
Journal/Book Title/Conference
Science
Volume
389
Issue
6761
Publisher
American Association for the Advancement of Science (AAAS)
Publication Date
8-14-2025
First Page
741
Last Page
746
Abstract
Copper-catalyzed radical C(sp3)‒N coupling has become a major focus in synthetic catalysis over the past decade. However, achieving this reaction manifold by using enzymes has remained elusive. In this study, we introduce a photobiocatalytic approach for radical benzylic C(sp3)‒N coupling using a copper-substituted nonheme enzyme. Using rhodamine B as a photoredox catalyst, we identified a copper-substituted phenylalanine hydroxylase that facilitates enantioconvergent decarboxylative amination between N-hydroxyphthalimide esters and anilines. Directed evolution remodeled the active site, resulting in high enantioselectivities for most substrates. On the basis of molecular modeling and mechanistic studies, we propose that the enzyme accommodates a copper-anilide complex that reacts with a benzylic radical. This study expands the scope of non-natural biocatalytic transition metal catalysis to copper-catalyzed radical coupling.
Recommended Citation
Xuzhong Shen et al. ,Enantioconvergent benzylic C(sp3)‒N coupling with a copper-substituted nonheme enzyme. Science 389, 741-746 (2025). DOI:10.1126/science.adt5986