Abstract
Dehydrogenation of an alkyl group via C–H activation forms a vinyl unit, which can act as a versatile stepping stone for diverse late-stage structural modifications at two adjacent sp3 carbon centres. However, enantioselective dehydrogenation via C–H metalation remains a challenge. Here we describe the realization of palladium-catalysed enantioselective β,γ-dehydrogenation of cycloalkyl amides enabled by chiral oxazoline–pyridone ligands to afford a wide range of highly elaborated carbocycles with exceptional enantioselectivity (>99% e.e.). Notably, the resulting chiral β,γ-unsaturated carbocycles are difficult to access via an inverse electron demand Diels–Alder reaction. Through ligand control, a tandem dehydrogenation and C–H olefination sequence also led to the formation of chiral β-alkylidene-γ-lactams. Remarkably, this catalyst is also compatible with biologically important natural products, including diterpenes and pentacyclic triterpenes, where each enantiomer of our chiral ligand enables site-selective modification at four distinct sites within the E ring.
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Data availability
The data that support the findings of this study are available within the Article and its Supplementary Information. The crystallographic data for the structures reported in this study for compounds 2ac, 2ad, 3r and 5c have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under accession numbers 2332771 (2ac), 2300388 (2ad), 2304156 (3r) and 2302270 (5c). These data can be obtained free of charge from the CCDC via www.ccdc.cam.ac.uk/data_request/cif.
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Acknowledgements
We acknowledge The Scripps Research Institute, the NIH (National Institute of General Medical Sciences grant R01GM084019) for financial support. J. Chen, B. Sanchez, J. Lee and Q. N. Wong from the Scripps Automated Synthesis Center are acknowledged for purification guidance. We acknowledge M. Gembicky, J. Bailey, E. Samolova and the UCSD Crystallography Facility for X-ray crystallographic analysis.
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Contributions
J.-Q.Y. conceived the concept. T.S. discovered and developed the dehydrogenation reaction. T.S. developed the substrate scope, T.Z. developed the chiral oxazoline–pyridone ligands. T.S., Z.Z. and J.-Q.Y. wrote the paper. J.-Q.Y. directed the project.
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Nature Synthesis thanks the anonymous reviewers for their contribution to the peer review of this work. Primary Handling Editor: Thomas West, in collaboration with the Nature Synthesis team.
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Supplementary information
Supplementary Information
Supplementary Tables 1–3, experimental procedures, additional reaction optimization, and characterization data.
Supplementary Data 1
Crystallographic data for compound 2ac, CCDC 2332771.
Supplementary Data 2
Crystallographic data for compound 2ad, CCDC 2300388.
Supplementary Data 3
Crystallographic data for compound 3r, CCDC 2304156.
Supplementary Data 4
Crystallographic data for compound 5c, CCDC 2302270.
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Sheng, T., Zhang, T., Zhuang, Z. et al. Synthesis of chiral carbocycles via enantioselective β,γ-dehydrogenation. Nat. Synth 3, 1550–1559 (2024). https://doi.org/10.1038/s44160-024-00628-z
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DOI: https://doi.org/10.1038/s44160-024-00628-z
