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A ring-distortion strategy to construct stereochemically complex and structurally diverse compounds from natural products

Nature Chemistry volume 5, pages 195–202 (2013)Cite this article

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Abstract

High-throughput screening is the dominant method used to identify lead compounds in drug discovery. As such, the makeup of screening libraries largely dictates the biological targets that can be modulated and the therapeutics that can be developed. Unfortunately, most compound-screening collections consist principally of planar molecules with little structural or stereochemical complexity, compounds that do not offer the arrangement of chemical functionality necessary for the modulation of many drug targets. Here we describe a novel, general and facile strategy for the creation of diverse compounds with high structural and stereochemical complexity using readily available natural products as synthetic starting points. We show through the evaluation of chemical properties (which include fraction of sp3 carbons, ClogP and the number of stereogenic centres) that these compounds are significantly more complex and diverse than those in standard screening collections, and we give guidelines for the application of this strategy to any suitable natural product.

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Figure 1
Figure 2: Application of ring-distortion reactions in the synthesis of complex and diverse small molecules from G.
Figure 3: Application of ring-distortion reactions in the synthesis of complex and diverse small molecules from A.
Figure 4: Application of ring-distortion reactions in the synthesis of complex and diverse small molecules from Q.
Figure 5: Comparison of compounds created by the CtD method with commercial screening collections.

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Acknowledgements

We thank the Office of Naval Research (N00014-09-1-0249) and the University of Illinois for support of this work. R.W.H. III is an American Cancer Society postdoctoral fellow. K.C.M. is a National Science Foundation predoctoral fellow and a Robert C. and Carolyn J. Springborn graduate fellow. M.F.R. is a member of the National Institutes of Health Chemistry–Biology Interface (Training Grant NRSA 1-T-32-GM070421). We thank D. Gray for the X-ray analysis of Q1, M. Brichacek for technical assistance with selected two-dimensional NMR experiments in addition to many helpful discussions and R. J. Rafferty for technical assistance. We also thank M. Ahmed and A. Al-khouja for the synthesis of various intermediates during these investigations.

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  1. Department of Chemistry, University of Illinois, Roger Adams Laboratory, 600 South Mathews, Urbana, 61801, Illinois, USA

    Robert W. Huigens III, Karen C. Morrison, Robert W. Hicklin, Timothy A. Flood Jr, Michelle F. Richter & Paul J. Hergenrother

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  1. Robert W. Huigens III
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Contributions

P.J.H. and R.W.H. III conceived the study. R.W.H. III designed and executed the synthesis of the A compound set and constructed libraries based on compounds A1, A2, A3, A5, A9, A12 and A15. K.C.M. designed and executed the synthesis of the G compound set and constructed libraries based on G6, G10 and G19. R.W.H. designed and executed the synthesis of the Q compound set and constructed the library based on Q1. T.A.F. performed computational analyses of all the compound sets discussed in this Article. M.F.R. constructed libraries of compounds A3, A12, G10 and G16. P.J.H. supervised this research and wrote this manuscript with the assistance of R.W.H. III, K.C.M., R.W.H. and T.A.F.

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Correspondence to Paul J. Hergenrother.

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Crystallographic data for compound Q1 (CIF 31 kb)

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Huigens III, R., Morrison, K., Hicklin, R. et al. A ring-distortion strategy to construct stereochemically complex and structurally diverse compounds from natural products. Nature Chem 5, 195–202 (2013). https://doi.org/10.1038/nchem.1549

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