Abstract
Cyclic organic molecules are common among natural products and pharmaceuticals1,2. In fact, the overwhelming majority of small-molecule pharmaceuticals contain at least one ring system, as they provide control over molecular shape, often increasing oral bioavailability while providing enhanced control over the activity, specificity and physical properties of drug candidates3,4,5. Consequently, new methods for the direct site and diastereoselective synthesis of functionalized carbocycles are highly desirable. In principle, molecular editing by C–H activation offers an ideal route to these compounds. However, the site-selective C–H functionalization of cycloalkanes remains challenging because of the strain encountered in transannular C–H palladation. Here we report that two classes of ligands—quinuclidine-pyridones (L1, L2) and sulfonamide-pyridones (L3)—enable transannular γ-methylene C–H arylation of small- to medium-sized cycloalkane carboxylic acids, with ring sizes ranging from cyclobutane to cyclooctane. Excellent γ-regioselectivity was observed in the presence of multiple β-C–H bonds. This advance marks a major step towards achieving molecular editing of saturated carbocycles: a class of scaffolds that are important in synthetic and medicinal chemistry3,4,5. The utility of this protocol is demonstrated by two-step formal syntheses of a series of patented biologically active small molecules, prior syntheses of which required up to 11 steps6.
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The data supporting the findings of this study are available within the article and its Supplementary Information files.
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Acknowledgements
We acknowledge The Scripps Research Institute and the National Institutes of Health (NIGMS grants 2R01GM084019 and F32GM143921) for their financial support. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank S. Chan for proofreading and providing helpful suggestions in preparing the manuscript. We thank G. Meng, S. Chan and N. Lam for helpful discussions. We thank Y. Lin for the preparation of ligand. J. Chen, B. Sanchez and Q. N. Wong are acknowledged for their assistance with liquid chromatography–mass spectrometry analysis and for separation of some products. We thank M. Gembicky, J. Bailey and the University of California San Diego Crystallography Facility for X-ray crystallographic analysis.
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Contributions
J.-Q.Y. conceived the concept. G.K. designed and prepared the quinuclidine-pyridone ligands. G.K. and T.S. discovered and developed the transannular γ-C–H arylation of cycloalkane carboxylic acids with ring sizes ranging from five to eight. D.A.S. and C.-Y.C. discovered and developed the transannular C–H arylation of cyclobutane carboxylic acids. G.K., D.A.S. and J.-Q.Y. wrote the manuscript. J.-Q.Y. directed the project.
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J.-Q.Y. and G.K. are inventors on a patent application related to the portion of this work covering 5- to 8-membered cycloalkane carboxylic acids and ligands L1 and L2 (US Patent application 63/483,314) filed by The Scripps Research Institute. The remaining authors declare no competing interests.
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Supplementary Sections 1–5
Including general information, an experimental section for transannular γ-methylene C–H activation, supplementary references, single crystal X-ray structures for compounds L1, 3c, 3s, 4ac, L2, 5b, 5k, 6a, 8a, C1 and C2, and 1H, 13C and 19F nuclear magnetic resonance (NMR) spectra data.
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Kang, G., Strassfeld, D.A., Sheng, T. et al. Transannular C–H functionalization of cycloalkane carboxylic acids. Nature 618, 519–525 (2023). https://doi.org/10.1038/s41586-023-06000-z
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DOI: https://doi.org/10.1038/s41586-023-06000-z
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