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Late-stage oxidative C(sp3)–H methylation


Frequently referred to as the ‘magic methyl effect’, installation of methyl groups, especially adjacent (α) to heteroatoms, has been shown to drastically increase the potency of bioactive molecules1–3. Current methylation methods display limited scope and have not been demonstrated in complex settings1. Here we report a regio- and chemoselective oxidative C(sp3)–H methylation method compatible with late-stage functionalization of drug scaffolds and natural products. This combines a highly site- and chemoselective C–H hydroxylation with a mild, functional-group-tolerant methylation. Using a small-molecule manganese catalyst Mn(CF3PDP) at low loading (substrate/catalyst = 200) afforded targeted C–H hydroxylation on heterocyclic cores, while preserving electron-neutral and electron-rich aryls. Fluorine- or Lewis-acid-assisted formation of reactive iminium or oxonium intermediates enabled the use of a mildly nucleophilic organoaluminum methylating reagent that preserves other electrophilic functionalities on the substrate. The late-stage C(sp3)–H methylation is demonstrated on 41 substrates housing 16 different medicinally important cores that include electron-rich aryls, heterocycles, carbonyls and amines. Eighteen pharmacologically relevant molecules with competing sites—including drugs (for example tedizolid) and natural products—are methylated site-selectively at the most electron rich, least sterically hindered position. Syntheses of two magic methyl substrates, an RORc inverse agonist and an S1P1 antagonist, are demonstrated for the first time via late-stage methylation from the drug or its advanced precursor. Additionally, an unprecedented remote methylation of the B-ring carbocycle of an abiraterone analog is shown. The ability to methylate such complex molecules at late stages will reduce synthetic effort and thereby expedite broader exploration of the magic methyl effect in pursuit of novel small molecule therapeutics and chemical probes.

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Correspondence to M. Christina White.

Supplementary information

Supplementary Information

This file contains the following sections: I. General information; II. Optimization data; III. Preparation and characterization of newly reported starting materials for Fig. 3; IV. Experimental procedures and compound characterization for Fig. 3; V. Preparation and characterization of newly reported starting materials for Fig. 4; VI. Experimental procedures and compound characterization for Fig. 4; VII. HPLC traces for the determination of product stereoretention; VIII. References; and IX. Spectral Data.

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Feng, K., Quevedo, R.E., Kohrt, J.T. et al. Late-stage oxidative C(sp3)–H methylation. Nature (2020).

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