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A diversity-oriented synthesis approach to macrocycles via oxidative ring expansion

Nature Chemical Biology volume 8, pages 358–365 (2012)Cite this article

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Abstract

Macrocycles are key structural elements in numerous bioactive small molecules and are attractive targets in the diversity-oriented synthesis of natural product–based libraries. However, efficient and systematic access to diverse collections of macrocycles has proven difficult using classical macrocyclization reactions. To address this problem, we have developed a concise, modular approach to the diversity-oriented synthesis of macrolactones and macrolactams involving oxidative cleavage of a bridging double bond in polycyclic enol ethers and enamines. These substrates are assembled in only four or five synthetic steps and undergo ring expansion to afford highly functionalized macrocycles bearing handles for further diversification. In contrast to macrocyclization reactions of corresponding seco acids, the ring expansion reactions are efficient and insensitive to ring size and stereochemistry, overcoming key limitations of conventional approaches to systematic macrocycle synthesis. Cheminformatic analysis indicates that these macrocycles access regions of chemical space that overlap with natural products, distinct from currently targeted synthetic drugs.

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Figure 1: Macrocyclic natural products and overall strategy for the diversity-oriented synthesis of macrolactones and macrolactams.
Figure 2: Modular approach to diverse polycyclic substrates for oxidative ring expansion.
Figure 3: Functionalization of macrocyclic scaffolds.
Figure 4: Cheminformatic analyses of macrocycle library.

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Acknowledgements

Dedicated to the memory of our colleague and mentor, David Y. Gin (1967–2011). We thank I. Shiina (Tokyo University of Science) for the generous gift of MNBA; G. Sukenick, H. Liu, H. Fang and S. Rusli (Memorial Sloan-Kettering Cancer Center Analytical Core Facility) for expert mass spectral analyses; and K. Kirschbaum (University of Toledo) for X-ray crystallographic analysis. Financial support from the NIH (P41 GM076267), Starr Foundation, Alfred P. Sloan Foundation (Research Fellowship to D.S.T.) and Deutscher Akademischer Austauschdienst (DAAD, postdoctoral fellowship to F.K.) is gratefully acknowledged.

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Author notes

  1. Felix Kopp and Christopher F Stratton: These authors contributed equally to this work.

Authors and Affiliations

  1. Molecular Pharmacology & Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Felix Kopp & Derek S Tan

  2. Tri-Institutional Training Program in Chemical Biology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Christopher F Stratton & Derek S Tan

  3. Chemical Biology Platform, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Lakshmi B Akella

  4. Tri-Institutional Research Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Derek S Tan

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  1. Felix Kopp
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Contributions

F.K., C.F.S. and D.S.T. designed the experiments. F.K. and C.F.S. carried out the synthetic experiments. C.F.S. carried out the PCA analysis. L.B.A. carried out the PMI analysis. F.K., C.F.S. and D.S.T. analyzed the data. F.K., C.F.S. and D.S.T. wrote the manuscript.

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Correspondence to Derek S Tan.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Methods and Supplementary Results (PDF 66330 kb)

Supplementary Data Set 1

PCA Data for Figure 4a–c and Supplementary Figure 5 (XLS 961 kb)

Supplementary Data Set 2

PMI Data for Figure 4d, Supplementary Figure 6 and Supplementary Figure 7 (XLS 1406 kb)

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Kopp, F., Stratton, C., Akella, L. et al. A diversity-oriented synthesis approach to macrocycles via oxidative ring expansion. Nat Chem Biol 8, 358–365 (2012). https://doi.org/10.1038/nchembio.911

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