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Asymmetric formation of γ-lactams via C–H amidation enabled by chiral hydrogen-bond-donor catalysts

Nature Catalysis volume 2, pages 219–227 (2019)Cite this article

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Abstract

Chiral γ-lactams are effective structural motifs found in numerous pharmaceutical agents. Despite their importance, current approaches mostly necessitate laborious synthetic steps employing pre-functionalized starting materials under demanding conditions. In this regard, asymmetric C−H amidation can provide an ideal platform for rapid construction of this valuable scaffold from unactivated materials, but unsolved issues have hampered the strategy. Here, we report iridium catalysts that overcome these challenges by utilizing chiral hydrogen-bond-donor ligands. The protocol makes use of easily accessible substrates derived from carboxylic acid, which display excellent efficiency and enantioselectivity towards direct amidation of prochiral sp3 C−H bonds. Desymmetrization of meso-substrates is also achieved, where two consecutive stereogenic centres are selectively introduced in a single transformation. Computational investigations reveal the presence of crucial hydrogen bonding in the stereo-determining transition states and spectroscopic analysis of the structural analogues further corroborate this non-covalent interaction.

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Fig. 1: Design of an asymmetric C–H amidation for chiral γ-lactam synthesis.
Fig. 2: Mechanistic challenges based on potential reaction working modes.
Fig. 3: Stereochemical model based on DFT calculations for the asymmetric C–H amidation.
Fig. 4: Experimental investigation of the intramolecular hydrogen bond between substrate and catalysts.
Fig. 5: Substrate scope and subsequent elaboration from obtained chiral lactams.

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Data availability

The X-ray crystallographic coordinates for the structures reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition nos. 1873622–1873624 and 1884674. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. All other data are available from the authors upon reasonable request.

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Acknowledgements

This research was supported by the Institute for Basic Science (IBS-R010-D1) in Korea. The authors thank D. Kim (Institute for Basic Science) for X-ray analysis.

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Authors and Affiliations

  1. Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea

    Yoonsu Park & Sukbok Chang

  2. Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon, Republic of Korea

    Yoonsu Park & Sukbok Chang

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Contributions

Y.P. and S.C. conceived and designed the project and wrote the manuscript. Y.P. carried out the experiments and DFT calculations. S.C. organized the research. Both authors analysed the data, discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Sukbok Chang.

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Competing interests

Y.P. and S.C. are inventors on a patent application no. KR10–2018–0174064, submitted by IBS and KAIST, which covers the preparation and application of the related transition metal catalysts.

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Supplementary information

Supplementary Information

Supplementary Methods, Supplementary Figures 1–36, Supplementary Discussion, Supplementary Tables 1–5, Supplementary Notes 1–2, Supplementary References

Supplementary Data 1

Cartesian coordinates for the optimized structures

CCDC reference 1873623

Crystallographic Data for compound 6

CCDC reference 1873624

Crystallographic Data for compound 31

CCDC reference 1884674

Crystallographic Data for compound Ir10

CCDC reference 1873622

Crystallographic Data for compound Ir13

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Park, Y., Chang, S. Asymmetric formation of γ-lactams via C–H amidation enabled by chiral hydrogen-bond-donor catalysts. Nat Catal 2, 219–227 (2019). https://doi.org/10.1038/s41929-019-0230-x

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