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Palladium-catalysed methylene C(sp3)–H lactamization and cycloamination enabled by chlorinated pyridine–pyridone ligands

Nature Synthesis (2024)Cite this article

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Abstract

Recent developments of bifunctional ligands have rapidly advanced palladium-catalysed C(sp3)–H activation reactions directed by native carboxylic acids. However, using this approach in inter- or intramolecular C(sp3)–H amination reactions is often hampered by N-coordination overriding the directing effect of the native carboxyl group. Here we report the design and development of chlorinated pyridine–pyridone ligands, which can overcome N-coordination and enable exclusive carboxylic-acid-directed lactamization and cycloamination of N-protected ω-amino acids. The compartmentalization of directed C(sp3)–H activation and C(sp3)–N bond formation in this reaction is distinct from existing C(sp3)–H amination approaches, in which both processes are directed by nitrogen. The protocols described in this report transform linear ω-amino acids into valuable cyclic β-amino acids possessing γ- and δ-lactam, pyrrolidine and tetrahydroquinoline scaffolds pertinent to drug discovery. The utility of this process was demonstrated by the formal synthesis of stemoamide.

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Fig. 1: C–H activation and the construction of lactams and cyclic amines.
Fig. 2: Overview of reaction development.
Fig. 3: Preliminary mechanistic investigations.
Fig. 4: Computational analysis of the origins of acid- versus amide-directed C–H activation.
Fig. 5: Substrate scope for the carboxylic-acid-directed β-C–H γ- and δ-lactamization reaction.
Fig. 6: Substrate scope for the carboxylic-acid-directed β-C–H cycloamination reaction.
Fig. 7: Applications of the C–H lactamization reaction in natural product synthesis and the use of chlorinated ligands to improve the related C–H lactonization reaction.

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Data availability

All data are in the Supplementary Information. Computational data are available on Figshare: https://doi.org/10.6084/m9.figshare.25345330.v1 (ref. 53).

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Acknowledgements

We thank M. Tomanik and K. Wu for proofreading and providing helpful suggestions in preparing the manuscript. We acknowledge The Scripps Research Institute, NIH (NIGMS, 2R01GM084019) and the Croucher Foundation (postdoctoral fellowship to H.S.S.C) for financial support.

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  1. Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA

    Hau Sun Sam Chan, Yilin Lu & Jin-Quan Yu

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Contributions

J.-Q.Y. and H.S.S.C. conceived the concept. H.S.S.C. discovered and developed the lactamization and cycloamination reactions, designed and synthesized ligands L2, L4, L7, L9, L10–L16 and L18, conducted preliminary mechanistic studies and finished the formal synthesis of stemoamide. Y.L. performed the computational studies. H.S.S.C. and J.-Q.Y. wrote the manuscript. J.-Q.Y. directed the project.

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Correspondence to Jin-Quan Yu.

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Competing interests

J.-Q.Y. and H.S.S.C. are inventors on a patent application related to this work (US Patent Application 63/551,249) filed by The Scripps Research Institute. The authors declare no other competing interests.

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Nature Synthesis thanks Chuan He and the other, anonymous, reviewer(s) 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 Figs. 1–21, Tables 1 and 2, synthetic procedures, computational modelling details, control experiments and NMR spectra.

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Chan, H.S.S., Lu, Y. & Yu, JQ. Palladium-catalysed methylene C(sp3)–H lactamization and cycloamination enabled by chlorinated pyridine–pyridone ligands. Nat. Synth (2024). https://doi.org/10.1038/s44160-024-00517-5

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