This month we highly recommend the organic chemistry paper from the Prof. Stahl’s group from the University of Wisconsin, together with Shane Krska from Merck, developed a new methodology for the direct C(sp3)-H methylation. This Ni&Photo-catalyzed transformation was validated on sophisticated scaffolds, show a late-stage functionalization potential, and a controlled regioselectivity (benzylic position or heteroatom α-position). A great toll that paves the way for rapid syntheses of “magic methylated” lead compounds analogues.

Abstract: 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(sp3)–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 β-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.

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

Author: Aristidis Vasilopoulos,Shane W. Krska,Shannon S. Stahl

Publication: Science

Publisher: The American Association for the Advancement of Science Date: Apr 23, 2021

We overcome drug discovery challenges using lastest synthetic tools

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