Catalytic undirected methylation of unactivated C(sp3)−H bonds suitable for complex molecules
Year: 2024
Type: article
Abstract: In pharmaceutical discovery, the “magic methyl” effect describes a substantial improvement in the pharmacological properties of a drug candidate with the incorporation of methyl groups. Therefore, to expedite the synthesis of methylated drug analogs, late-stage, undirected methylations of C(sp3)−H bonds in complex molecules would be valuable. However, current methods for site-selective methylations are limited to activated C(sp3)−H bonds. Here we describe a site-selective, undirected methylation of unactivated C(sp3)−H bonds, enabled by photochemically activated peroxides and a nickel(II) complex whose turnover is enhanced by an ancillary ligand. The methodology displays compatibility with a wide range of functional groups and a high selectivity for tertiary C−H bonds, making it suitable for the late-stage methylation of complex organic compounds that contain multiple alkyl C−H bonds, such as terpene natural products, peptides, and active pharmaceutical ingredients. Overall, this method provides a synthetic tool to explore the “magic methyl” effect in drug discovery.
Source: Nature Communications
Authors: Jin-Fay Tan, Yi Cheng Kang, John F. Hartwig
Institution: University of California, Berkeley
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: gold
Estimated APC paid: $5,171
Awards: Acquisition of a Cryoprobe and Related Accessories for a 600 MHz NMR Spectrometer to Support Health Research Activities at the University of California, Berkeley, G3203542529, G5766157962, G7028801745, Discovery and Development of Organic Reactions Catalyzed by Transition Metals Valuable for Medicinal Chemistry, Site-Selective, Late Stage Functionalizations of Unactivated C(sp3)-H Bonds in Complex Molecules, G9000331086
OpenAlex ID: W4402923343