Journal
SCIENCE
Volume 353, Issue 6303, Pages 1014-1018Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aaf7783
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Funding
- National Basic Research Program of China (973) [2015CB856600]
- National Natural Science Foundation of China [21225210, 21421091, 21532009, 21472217]
- National Institutes of Health [F31-GM116443]
- Department of Energy [DE-FG02-05ER15690]
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Direct methods for stereoselective functionalization of sp(3)-hybridized carbon-hydrogen [C(sp(3))-H] bonds in complex organic molecules could facilitate much more efficient preparation of therapeutics and agrochemicals. Here, we report a copper-catalyzed radical relay pathway for enantioselective conversion of benzylic C-H bonds into benzylic nitriles. Hydrogen-atom abstraction affords an achiral benzylic radical that undergoes asymmetric C(sp(3))-CN bond formation upon reaction with a chiral copper catalyst. The reactions proceed efficiently at room temperature with the benzylic substrate as limiting reagent, exhibit broad substrate scope with high enantioselectivity (typically 90 to 99% enantiomeric excess), and afford products that are key precursors to important bioactive molecules. Mechanistic studies provide evidence for diffusible organic radicals and highlight the difference between these reactions and C-H oxidations mediated by enzymes and other catalysts that operate via radical rebound pathways.
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