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Stereoselective construction of β-, γ- and δ-lactam rings via enzymatic C–H amidation

Nature Catalysis volume 7, pages 65–76 (2024)Cite this article

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A preprint version of the article is available at arXiv.

Abstract

Lactam rings are found in many biologically active natural products and pharmaceuticals, including important classes of antibiotics. Methods for the asymmetric synthesis of these molecules are therefore highly desirable, particularly through the selective functionalization of unreactive aliphatic C–H bonds. Here we show the development of a strategy for the asymmetric synthesis of β-, γ- and δ-lactams via the haemoprotein-catalysed intramolecular C–H amidation of readily accessible dioxazolone reagents. Engineered myoglobin variants serve as excellent biocatalysts for this transformation, yielding the desired lactam products in high yields with high enantioselectivity and on a preparative scale. Mechanistic and computational studies were conducted to elucidate the nature of the C–H amidation and enantiodetermining steps and provide insights into the protein-mediated control of the regioselectivity and stereoselectivity. Additionally, an alkaloid natural product and a drug molecule were synthesized chemoenzymatically in fewer steps (7–8 versus 11–12) than previously reported, further demonstrating the power of biosynthetic strategies for the preparation of complex bioactive molecules.

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Fig. 1: Asymmetric lactam synthesis via enzyme-catalysed C(sp3)–H amidation.
Fig. 2: Biocatalytic intramolecular C(sp3)‒H amidation of dioxazolones.
Fig. 3: Substrate scope for Mb*-catalysed C–H amidation reaction.
Fig. 4: Mechanistic studies.
Fig. 5: Computational analysis of the enantio- and regiocontrol.
Fig. 6: Applications of the Mb*-catalysed C–H amidation reaction.

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Data availability

The crystallographic data of the small molecules have been deposited at the Cambridge Crystallographic Data Centre (CCDC) under deposition numbers CCDC 1893087 (2a), 2157011 (2m), 2157007 (4j) and 2157010 (6c). The data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

This work was supported by the US National Institute of Health (grant no. GM098628, to R.F.) and Cancer Prevention and Research Institute of Texas (CPRIT, RR230018 to R.F.). R.F. acknowledges endowed professorship support from the Robert A. Welch Foundation. D.A.V. acknowledges support from the National Science Foundation Graduate Fellowship Program. K.N.H. acknowledges support from the US National Science Foundation (grant no. CHE-1764328), and the Natural Science Foundation of China (grant no. 22103060) provided the computational resources used in the QM analyses. We are grateful to W. Brennessel (University of Rochester) for assistance with the crystallographic analyses. MS and X-ray instrumentation at the University of Rochester are supported by US National Science Foundation (grant nos. CHE-0946653 and CHE-1725028) and the US National Institute of Health (grant no. S10OD030302).

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Author notes

  1. Satyajit Roy & Rudi Fasan

    Present address: Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, TX, USA

  2. David A. Vargas

    Present address: Process Research and Development, Merck, Rahway, NJ, USA

  3. These authors contributed equally: Satyajit Roy, David A. Vargas, Pengchen Ma.

Authors and Affiliations

  1. Department of Chemistry, University of Rochester, Rochester, NY, USA

    Satyajit Roy, David A. Vargas & Rudi Fasan

  2. Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA

    Pengchen Ma, Arkajyoti Sengupta & K. N. Houk

  3. School of Chemistry, Xi’an Key Laboratory of Sustainable Energy Materials Chemistry, MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, Xi’an Jiaotong University, Xi’an, China

    Pengchen Ma

  4. Environment Research Institute, Shandong University, Qingdao, People’s Republic of China

    Ledong Zhu

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Contributions

D.A.V., S.R. and R.F. conceived the project and designed the experiments. S.R. and D.A.V. performed the experiments with guidance from R.F. K.N.H. mentored P.M., A.S. and L.Z. in the molecular dynamics and quantum mechanics calculations and contributed to the writing of the mechanistic parts of the paper. D.A.V., S.R., A.S.and R.F wrote the paper. All authors discussed the results and contributed to the final paper.

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Correspondence to K. N. Houk or Rudi Fasan.

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Nature Catalysis thanks Sabine Flitsch and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary methods, Computational analyses, Crystal data collection, NMR spectra, tables, figures and references.

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Supplementary Data

1Initial and final configurations of MD trajectories.

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Roy, S., Vargas, D.A., Ma, P. et al. Stereoselective construction of β-, γ- and δ-lactam rings via enzymatic C–H amidation. Nat Catal 7, 65–76 (2024). https://doi.org/10.1038/s41929-023-01068-2

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