Room-temperature enantioselective C–H iodination via kinetic resolution

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Science  24 Oct 2014:
Vol. 346, Issue 6208, pp. 451-455
DOI: 10.1126/science.1258538

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Ensuring handedness when breaking C-H bonds

Many organic compounds are chiral: They manifest two distinct mirror-image variants, or enantiomers. Kinetic resolution can transform one enantiomer to a desired product while leaving its mirror image unmodified. Chu et al. applied this strategy to a reaction that replaces aryl carbon–hydrogen bonds with carbon-iodine bonds. They used a chiral palladium catalyst that reacts selectively with just one of two enantiomers of various benzylamine derivatives. In medicinal chemistry, such selective synthesis of individual enantiomers is essential for screening interactions with chiral biomolecules such as proteins.

Science, this issue p. 451


Asymmetric carbon-hydrogen (C–H) activation reactions often rely on desymmetrization of prochiral C–H bonds on the same achiral molecule, using a chiral catalyst. Here, we report a kinetic resolution via palladium-catalyzed enantioselective C–H iodination in which one of the enantiomers of a racemic benzylic amine substrates undergoes faster aryl C–H insertion with the chiral catalysts than the other. The resulting enantioenriched C–H functionalization products would not be accessible through desymmetrization of prochiral C–H bonds. The exceedingly high relative rate ratio (kfast/kslow up to 244), coupled with the subsequent iodination of the remaining enantiomerically enriched starting material using a chiral ligand with the opposite configuration, enables conversion of both substrate enantiomers into enantiomerically pure iodinated products.

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