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Biomimetic diversity-oriented synthesis of benzannulated medium rings via ring expansion

Nature Chemical Biology volume 9, pages 21–29 (2013)Cite this article

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Abstract

Nature has exploited medium-sized 8- to 11-membered rings in a variety of natural products to address diverse and challenging biological targets. However, owing to the limitations of conventional cyclization-based approaches to medium-ring synthesis, these structures remain severely underrepresented in current probe and drug discovery efforts. To address this problem, we have established an alternative, biomimetic ring expansion approach to the diversity-oriented synthesis of medium-ring libraries. Oxidative dearomatization of bicyclic phenols affords polycyclic cyclohexadienones that undergo efficient ring expansion to form benzannulated medium-ring scaffolds found in natural products. The ring expansion reaction can be induced using three complementary reagents that avoid competing dienone-phenol rearrangements and is driven by rearomatization of a phenol ring adjacent to the scissile bond. Cheminformatic analysis of the resulting first-generation library confirms that these molecules occupy chemical space overlapping with medium-ring natural products and distinct from that of synthetic drugs and drug-like libraries.

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Figure 1: Overall strategy and precedents for the synthesis of benzannulated medium rings.
Figure 2: Proposed mechanisms for aromatization-driven ring expansion of 5 to benzannulated medium rings 6, 7, 8 and for formation of alternate tricycles 9 and 10.
Figure 3: Downstream modifications of ODRE-derived benzannulated medium-ring scaffolds.

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Acknowledgements

This work is dedicated to the memory of our colleague and mentor, David Y. Gin (1967–2011). We thank D. Boger for helpful discussions; C. Stratton for assistance with PCA calculations; J. Njar∂arson for providing drug structures; and G. Sukenick, H. Liu, H. Fang and S. Rusli for expert mass spectral analyses. Instant JChem was generously provided by ChemAxon. Financial support from the US National Institutes of Health (P41 GM076267 to D.S.T., P41 GM076267-03S1 to R.A.B. and T32 CA062948-Gudas to T.A.W.), W.H. Goodwin and A. Goodwin and the Commonwealth Foundation for Cancer Research, the Memorial Sloan-Kettering Cancer Center Experimental Therapeutics Center and the Tri-Institutional Stem Cell Initiative is gratefully acknowledged.

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Authors and Affiliations

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

    Renato A Bauer & Derek S Tan

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

    Todd A Wenderski & Derek S Tan

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

    Derek S Tan

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  1. Renato A Bauer
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Contributions

R.A.B., T.A.W. and D.S.T. designed the experiments, analyzed the data and wrote the manuscript. R.A.B. and T.A.W. performed the synthesis and characterization. T.A.W. performed the molecular modeling studies. R.A.B. performed the PCA analysis.

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Correspondence to Derek S Tan.

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Supplementary Results, Supplementary Notes 1–3 (PDF 90779 kb)

Supplementary Data Set 1

PCA analysis (XLS 7676 kb)

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Bauer, R., Wenderski, T. & Tan, D. Biomimetic diversity-oriented synthesis of benzannulated medium rings via ring expansion. Nat Chem Biol 9, 21–29 (2013). https://doi.org/10.1038/nchembio.1130

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