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Chemoselective methylene oxidation in aromatic molecules

Abstract

Despite significant progress in the development of site-selective aliphatic C–H oxidations over the past decade, the ability to oxidize strong methylene C–H bonds in the presence of more oxidatively labile aromatic functionalities remains a major unsolved problem. Such chemoselective reactivity is highly desirable for enabling late-stage oxidative derivatizations of pharmaceuticals and medicinally important natural products that often contain such functionality. Here, we report a simple manganese small-molecule catalyst Mn(CF3–PDP) system that achieves such chemoselectivity via an unexpected synergy of catalyst design and acid additive. Preparative remote methylene oxidation is obtained in 50 aromatic compounds housing medicinally relevant halogen, oxygen, heterocyclic and biaryl moieties. Late-stage methylene oxidation is demonstrated on four drug scaffolds, including the ethinylestradiol scaffold where other non-directed C–H oxidants that tolerate aromatic groups effect oxidation at only activated tertiary benzylic sites. Rapid generation of a known metabolite (piragliatin) from an advanced intermediate is demonstrated.

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Fig. 1: Enzymatic and small-molecule approaches for C–H oxidation.
Fig. 2: Chemoselective methylene C–H oxidation.
Fig. 3: Late-stage methylene hydroxylation of synthetic and natural product, aromatic drugs derivatives.

Data availability

Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre (CCDC) under deposition nos. CCDC 1869257 for (S,S)-5, CCDC 1869258 for 73, CCDC 1869259 for 74 and CCDC 1869260 for (R,R)-S2. Copies of the data can be obtained free of charge from www.ccdc.cam.ac.uk/structures/. All other data supporting the findings of this study are available within the Article and its Supplementary Information, or from the corresponding author upon reasonable request.

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Acknowledgements

Financial support for this work was provided by the NIH NIGMS Maximizing Investigators’ Research Award MIRA (R35 GM122525). The authors acknowledge The Uehara Memorial Foundation for a fellowship to T.N. and Conselho Nacional de Desenvolvimento Científico e Tecnológico for a fellowship to E.C.L. (proc. no. 234643/2014-5). The authors thank L. Zhu for assistance with NMR spectroscopy, D. Gray and T. Woods for X-ray crystallographic studies, and C. Delaney for preliminary studies on basic nitrogen-containing compounds. The authors also thank C. Wendell, K. Feng and W. Liu for checking the procedures. The data reported in this paper are tabulated in the Supplementary Information.

Author information

Affiliations

Authors

Contributions

M.C.W. and J.Z. conceived and designed the project and wrote the manuscript. J.Z., T.N. and E.C.L. conducted the experiments and analysed the data. 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 on the Mn(CF3–PDP) catalyst for methylene oxidation in aromatic molecules.

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Supplementary information

Supplementary Information

Supplementary experimental data, synthetic procedures, chemical compound characterization data and Supplementary Figs 1–4

Crystallographic data

CIF for compound S2. CCDC reference 1869260

Crystallographic data

CIF for compound 5. CCDC reference 1869257

Crystallographic data

CIF for compound 73. CCDC reference 1869258

Crystallographic data

CIF for compound 74. CCDC reference 1869259

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Zhao, J., Nanjo, T., de Lucca, E.C. et al. Chemoselective methylene oxidation in aromatic molecules. Nature Chem 11, 213–221 (2019). https://doi.org/10.1038/s41557-018-0175-8

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