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A catalytic process enables efficient and programmable access to precisely altered indole alkaloid scaffolds

Nature Chemistry (2024)Cite this article

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Abstract

A compound’s overall contour impacts its ability to elicit biological response, rendering access to distinctly shaped molecules desirable. A natural product’s framework can be modified, but only if it is abundant and contains suitably modifiable functional groups. Here we introduce a programmable strategy for concise synthesis of precisely altered scaffolds of scarce bridged polycyclic alkaloids. Central to our approach is a scalable catalytic multi-component process that delivers diastereo- and enantiomerically enriched tertiary homoallylic alcohols bearing differentiable alkenyl moieties. We used one product to launch progressively divergent syntheses of a naturally occurring alkaloid and its precisely expanded, contracted and/or distorted framework analogues (average number of steps/scaffold of seven). In vitro testing showed that a skeleton expanded by one methylene in two regions is cytotoxic against four types of cancer cell line. Mechanistic and computational studies offer an account for several unanticipated selectivity trends.

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Fig. 1: Bridged polycyclic indole alkaloids, the foundational multi-component process and its applicability.
Fig. 2: Catalyst screening and the scope of the multi-component process.
Fig. 3: Diastereo- and enantioselective synthesis of the primary hub and some surprising observations along the way.
Fig. 4: Progressively divergent conversion of the primary hub to secondary and tertiary hubs.
Fig. 5: Synthesis of the NP and precisely altered scaffolds and in vitro testing.
Fig. 6: DFT studies offer insight regarding several unexpected selectivity trends.

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Data availability

All data in support of the findings of this study are available within the article and its Supplementary Information. Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2237819 (7b) and 1874716 (8). Source data are provided with this paper.

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Acknowledgements

The methodological aspects of this work were funded by the NIH (grant R35 GM-130395 to A.H.H.). Support for applications to synthesis of NP and the corresponding analogues was provided by the CNRS, the ANR (project PRACTACAL to A.H.H.), the Jean-Marie Lehn Foundation for Chemistry Research (University of Strasbourg, to A.H.H.) and the Circle Gutenberg Foundation (2020 Chair for A.H.H.). Additional support was provided by the University of Illinois (for P.J.H.) and the NIH (grant R35 GM-128779 to P.L.). We thank the Shanghai Institute of Organic Chemistry and Solvay, S.A. for a postdoctoral and a predoctoral fellowship to Y.H. and X.L., respectively. In vitro testing was performed at the University of Illinois, Urbana-Champain. DFT and PMI studies were carried out at the Center for Research Computing at the University of Pittsburgh, Bridges 2 supercomputer at the San Diego Supercomputer Center through allocation TG-CHE140139 from the Advanced Cyberinfrastructure Ecosystem: Services and Support (ACCESS) programme, funded by NSF grants. We are grateful to F. Romiti, M. Formica, S. Ng, S. Xu and A. Nikbakht for helpful discussions.

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Author notes

  1. These authors contributed equally: Youming Huang, Xinghan Li.

Authors and Affiliations

  1. Supramolecular Science and Engineering Institute, University of Strasbourg, CNRS, Strasbourg, France

    Youming Huang, Xinghan Li & Amir H. Hoveyda

  2. Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, MA, USA

    Youming Huang, Xinghan Li & Amir H. Hoveyda

  3. Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA

    Binh Khanh Mai & Peng Liu

  4. Department of Chemistry, Carl Woese Institute for Genomic Biology, University of Illinois, Urbana, IL, USA

    Emily J. Tonogai, Amanda J. Smith & Paul J. Hergenrother

  5. Cancer Center at Illinois, University of Illinois, Urbana, IL, USA

    Paul J. Hergenrother

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Contributions

A.H.H., X.L. and Y.H. designed and developed the catalytic multi-component method and prepared the natural products and skeletal analogues. P.J.H., E.J.T. and A.J.S. performed the in vitro testing. P.L. and B.K.M. designed and performed the DFT studies. A.H.H. conceived the project, directed the investigations and wrote the paper, and the other authors provided editorial advice.

Corresponding authors

Correspondence to Paul J. Hergenrother, Peng Liu or Amir H. Hoveyda.

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Nature Chemistry thanks Kevin Kou and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–12 and Tables 1–8.

Reporting Summary

Supplementary Data 1

Crystallographic data for compound 7b; CCDC reference 2237819.

Supplementary Data 2

Crystallographic data for compound 7b; CCDC reference 1874716.

Supplementary Data 3

The xyz coordinates of computed structures.

Source data

Source Data Fig. 5

Statistical source data for Fig. 5f.

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Huang, Y., Li, X., Mai, B.K. et al. A catalytic process enables efficient and programmable access to precisely altered indole alkaloid scaffolds. Nat. Chem. (2024). https://doi.org/10.1038/s41557-024-01455-7

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