4.8 Article

C(sp3)-H methylation enabled by peroxide photosensitization and Ni-mediated radical coupling

Journal

SCIENCE
Volume 372, Issue 6540, Pages 398-+

Publisher

AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.abh2623

Keywords

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Funding

  1. NIH [R01 GM126832, R35 GM134929, 1S10 OD020022-1]
  2. NSF [CHE-1048642]

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The research presents a synthetic method that allows for direct methylation of C(sp(3))-H bonds in drug-like molecules and pharmaceutical building blocks, leading to changes in potency, selectivity, and metabolic stability.
The magic methyl effect describes the change in potency, selectivity, and/or metabolic stability of a drug candidate associated with addition of a single methyl group. We report a synthetic method that enables direct methylation of C(sp(3))-H bonds in diverse drug-like molecules and pharmaceutical building blocks. Visible light-initiated triplet energy transfer promotes homolysis of the O-O bond in di-tert-butyl or dicumyl peroxide under mild conditions. The resulting alkoxyl radicals undergo divergent reactivity, either hydrogen-atom transfer from a substrate C-H bond or generation of a methyl radical via beta-methyl scission. The relative rates of these steps may be tuned by varying the reaction conditions or peroxide substituents to optimize the yield of methylated product arising from nickel-mediated cross-coupling of substrate and methyl radicals.

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