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Late-stage oxidative C(sp3)–H methylation

Abstract

Frequently referred to as the ‘magic methyl effect’, the installation of methyl groups—especially adjacent (α) to heteroatoms—has been shown to dramatically increase the potency of biologically active molecules1,2,3. However, existing methylation methods show limited scope and have not been demonstrated in complex settings1. Here we report a regioselective and chemoselective oxidative C(sp3)–H methylation method that is compatible with late-stage functionalization of drug scaffolds and natural products. This combines a highly site-selective and chemoselective C–H hydroxylation with a mild, functional-group-tolerant methylation. Using a small-molecule manganese catalyst, Mn(CF3PDP), at low loading (at a substrate/catalyst ratio of 200) affords 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 enables the use of a mildly nucleophilic organoaluminium methylating reagent that preserves other electrophilic functionalities on the substrate. We show this late-stage C(sp3)–H methylation 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. We demonstrate the syntheses of two magic methyl substrates—an inverse agonist for the nuclear receptor RORc and an antagonist of the sphingosine-1-phosphate receptor-1—via late-stage methylation from the drug or its advanced precursor. We also show a remote methylation of the B-ring carbocycle of an abiraterone analogue. 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 new small-molecule therapeutics and chemical probes.

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Fig. 1: C(sp3)–H methylation.
Fig. 2: Reaction development.
Fig. 3: Ten different heterocyclic cores, commonly found in pharmaceuticals, explored in the Mn(CF3PDP) (1)-catalysed C–H oxidative methylation.
Fig. 4: Application of oxidative methylation for late-stage functionalization.

Data availability

The data that support the findings of this study are available in the Supplementary Information and from the corresponding author upon reasonable request.

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Acknowledgements

Financial support for this work was provided by the National Institute of General Medical Sciences (NIGMS) Maximizing Investigators’ Research Award (MIRA; grant R35 GM122525), and from Pfizer to study the modifications of natural products and medicinal compounds. We thank L. Zhu and the University of Illinois School of Chemical Science (SCS) nuclear magnetic resonance (NMR) laboratory for assistance with NMR spectroscopy, and B. Budaitis for checking the procedure in Fig. 3, molecule 8. The Bruker 500-Mz NMR spectrometer was obtained with the financial support of the Roy J. Carver Charitable Trust, Muscatine, IA, USA.

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Contributions

K.F. and R.E.Q. conducted the experiments and analysed the data. M.C.W., K.F. and R.E.Q. wrote the manuscript. M.C.W., K.F., R.E.Q., J.T.K., M.S.O. and U.R. designed the project. All authors provided comments on the experiments and manuscript during its preparation.

Corresponding author

Correspondence to M. Christina White.

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Competing interests

The University of Illinois has filed a patent application (number 16/569,492) on the Mn(CF3PDP) catalyst that lists M.C.W. as an inventor.

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Extended data figures and tables

Extended Data Table 1 Reaction optimization

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 Figure 3; IV. Experimental procedures and compound characterization for Figure 3; V. Preparation and characterization of newly reported starting materials for Figure 4; VI. Experimental procedures and compound characterization for Figure 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 580, 621–627 (2020). https://doi.org/10.1038/s41586-020-2137-8

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